Methods of Using PI3K and MEK Modulators

ABSTRACT

The invention provides methods of treating cancer with a combination of compounds which inhibit kinases, more specifically MEK and PI3K.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to methods of treating cancer with a combinationof compounds that modulate protein kinase enzymatic activities and theresultant modulation of cellular activities (such as proliferation,differentiation, programmed cell death, migration, chemoinvasion andmetabolism). In particular, this invention relates to a compound thatinhibits mitogen activated protein kinase (MEK) used in combination witha compound that inhibits phosphatidylinositol 3-kinase (PI3K) signalingpathways.

2. State of the Art

Improvements in the specificity of agents used to treat cancer is ofconsiderable interest because of the therapeutic benefits which would berealized if the side effects associated with the administration of theseagents could be reduced. Traditionally, dramatic improvements in thetreatment of cancer are associated with identification of therapeuticagents acting through novel mechanisms.

Protein kinases are enzymes that catalyze the phosphorylation ofproteins, in particular, hydroxy groups on tyrosine, serine andthreonine residues of proteins. The consequences of this seeminglysimple activity are staggering; cell differentiation and proliferation;i.e., virtually all aspects of cell life in one-way or another depend onprotein kinase activity. Furthermore, abnormal protein kinase activityhas been related to a host of disorders, ranging from relativelynon-life threatening diseases such as psoriasis to extremely virulentdiseases such as glioblastoma (brain cancer).

Protein kinases can be categorized as receptor type or non-receptortype. Receptor-type tyrosine kinases have an extracellular, atransmembrane, and an intracellular portion, while non-receptor typetyrosine kinases are wholly intracellular. They are comprised of a largenumber of transmembrane receptors with diverse biological activity. Infact, about 20 different subfamilies of receptor-type tyrosine kinaseshave been identified. One tyrosine kinase subfamily, designated the HERsubfamily, is comprised of EGFR (HER1), HER2, HER3, and HER4. Ligands ofthis subfamily of receptors identified so far include epithelial growthfactor, TGF-alpha, amphiregulin, HB-EGF, betacellulin and heregulin.Another subfamily of these receptor-type tyrosine kinases is the insulinsubfamily, which includes INS-R, IGF-IR, and IR-R. The PDGF subfamilyincludes the PDGF-alpha and beta receptors, CSFIR, c-kit and FLK-II. Inaddition, there is the FLK family, which is comprised of the kinaseinsert domain receptor (KDR), fetal liver kinase-1 (FLK-1), fetal liverkinase-4 (FLK-4) and the fms-like tyrosine kinase-1 (flt-1). The PDGFand FLK families are usually considered together due to the similaritiesof the two groups. For a detailed discussion of the receptor-typetyrosine kinases, see Plowman et al., DN&P 7(6): 334-339, 1994, which ishereby incorporated by reference.

The non-receptor type of tyrosine kinases is also comprised of numeroussubfamilies, including Src, Frk, Btk, Csk, Abl, Zap70, Fes/Fps, Fak,Jak, Ack, and LIMK. Each of these subfamilies is further sub-dividedinto varying receptors. For example, the Src subfamily is one of thelargest and includes Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr, and Yrk.The Src subfamily of enzymes has been linked to oncogenesis. For a moredetailed discussion of the non-receptor type of tyrosine kinases, seeBolen, Oncogene, 8:2025-2031 (1993), which is hereby incorporated byreference.

Since protein kinases and their ligands play critical roles in variouscellular activities, deregulation of protein kinase enzymatic activitycan lead to altered cellular properties, such as uncontrolled cellgrowth associated with cancer. In addition to oncological indications,altered kinase signaling is implicated in numerous other pathologicaldiseases. These include, but are not limited to: immunologicaldisorders, cardiovascular diseases, inflammatory diseases, anddegenerative diseases. Therefore, both receptor and non-receptor proteinkinases are attractive targets for small molecule drug discovery.

One particularly attractive target for small-molecule modulation, withrespect to antiangiogenic and antiproliferative activity is MEK. TheMEK-ERK signal transduction cascade is a conserved pathway whichregulates cell growth, proliferation, differentiation, and apoptosis inresponse to growth factors, cytokines, and hormones. This pathwayoperates downstream of Ras which is often upregulated or mutated inhuman tumors. It has been demonstrated that MEK is a critical effectorof Ras function. A large portion of human cancers, including 80%pancreatic, 50% colorectal, and 40% lung cancers, harbor activating Rasmutations. It has been shown that inhibition of the ERK pathway, and inparticular inhibition of MEK kinase activity, results in anti-metastaticand anti-angiogenic effects largely due to a reduction of cell-cellcontact and motility as well as downregulation of vascular endothelialgrowth factor (VEGF) expression. Furthermore, expression of dominantnegative MEK, or ERK reduced the transforming ability of mutant Ras asseen in cell culture and in primary and metastatic growth of human tumorxenografts in vivo. Therefore, the MEK-ERK signal transduction pathwayis an appropriate pathway to target for therapeutic intervention.

Accordingly, the identification of small-molecule compounds thatspecifically inhibit, regulate and/or modulate the signal transductionof kinases, particularly MEK, is desirable as a means to treat orprevent disease states associated with cancer and is an object of thisinvention.

Phosphatidylinositol 3-kinase (PI3Kα), a dual specificity proteinkinase, is composed of an 85 kDa regulatory subunit and a 110 kDacatalytic subunit. The protein encoded by this gene represents thecatalytic subunit, which uses ATP to phosphorylate PtdIns, PtdIns4P andPtdIns(4,5)P2. PI3Kα has been implicated in the control of cytoskeletalreorganization, apoptosis, vesicular trafficking, proliferation anddifferentiation processes. Increased copy number and expression ofPIK3CA is associated with a number of malignancies such as ovariancancer, cervical cancer, breast cancer, colorectal cancer, andglioblastomas, among others. The tumor suppressor PTEN inhibits cellgrowth through multiple mechanisms. PTEN can dephosphorylate PIP3, themajor product of PIK3CA. PIP3, in turn, is required for translocation ofprotein kinase B (AKT1, PKB) to the cell membrane, where it isphosphorylated and activated by upstream kinases. The effect of PTEN oncell death is mediated through the PIK3CA/AKT1 pathway.

Thus, an object of this invention is the identification ofsmall-molecule compounds that specifically inhibit, regulate and/ormodulate the signal transduction of kinases, particularlyphosphatidylinositol 3-kinase, in order to treat, prevent, and/orinhibit diseases and conditions associated with cancers.

Combination therapy has been commonly utilized to overcome drugresistance. Clinical trials of dasatinib or nilotinib (AMN-107) incombination with the current standard CML therapy, ie., imatinib(Gleevec®), are ongoing (ClinicalTrials.gov) Dasatinib in combinationwith Gleevec® has shown improved efficacy against various Abl mutantsexcept for T3151 in preclinical studies (O'Hare T, Walters D K,Stoffregen E P, et al., “Combined Abl inhibitor therapy for minimizingdrug resistance in chronic mycloid leukemia: Src/Abl inhibitors arecompatible with imatinib”, Clin Cancer Res. 11, 6987-6993 (2005)).Recently, specific mutations in B-RAF have been shown to confer reducedsensitivity to treatment of cells and tumors with compounds that inhibitMEK (Solit et al. Nature online, pgs 1-5 Nov. 6, 2005). Combinationtherapys treating multiple kinases pathways should eliminate thisreduced sensitivity.

SUMMARY OF THE INVENTION

This invention provides a method of using an MEK inhibitor of Formula I,Ia, Ic, Id, II, III, IV, or V in combination with a PI3K inhibitor ofFormula VI, VIa, VIb, or VII, or in combination with a PI3K inhibitor ofFormula VIII, VIIIa, VIIIb, IX, X, XI or XI for the treatment ofhyperproliferative disorders, such as cancers.

In one embodiment, in section I an MEK inhibitor of Formula I is asfollows:

and optionally a pharmaceutically acceptable salt or solvate thereof,wherein the A ring, X, R¹, R², R⁴, R⁵, R⁶, and R⁷ are as defined belowin Section I.

In one embodiment, in section II a PI3K inhibitor of Formula VI is asfollows:

and optionally a pharmaceutically acceptable salt hydrate or solvatethereof, wherein X, R¹, R², R⁴, R⁵, and R⁶ are as defined below inSection II.

In one embodiment, in section III a PI3K inhibitor of Formula VIII is asfollows:

and optionally a pharmaceutically acceptable salt hydrate or solvatethereof, wherein W¹, W², W³, W⁴, A, X, R⁴, and B are as defined inSection III.

The invention encompasses using the MEK inhibitor disclosed in Section Iin combination with the PI3K inhibitor of section II or section III totreat a hyperproliferative diseases and disorders and in particularcancers comprising administering to a patient a compound of Formula I,Ia, Ic, Id, II, III, IV, or V, with a compound of the Formula VI, VIa,VIb, or VII, or a compound of the Formula VIII, VIIIa, VIIIb, IX, X, orXI, or a pharmaceutical composition thereof.

The foregoing merely summarizes certain embodiments of the invention andis not intended to be limiting in nature. These embodiments and otherembodiments and embodiments are described more fully below. The patentand scientific literature referred to herein establishes knowledge thatis available to those with skill in the art. The issued patents,applications, and references that are cited herein are herebyincorporated by reference to the same extent as if each was specificallyand individually indicated to be incorporated by reference. In the caseof inconsistencies, the present disclosure will prevail.

DETAILED DESCRIPTION OF THE INVENTION

The following applies to all three sections.

“Yield” for each of the reactions described herein is expressed as apercentage of the theoretical yield.

Some of the compounds of the invention may have imino, amino, oxo orhydroxy substituents off aromatic heterocyclyl systems. For purposes ofthis disclosure, it is understood that such imino, amino, oxo or hydroxysubstituents may exist in their corresponding tautomeric form, i.e.,amino, imino, hydroxy or oxo, respectively.

Compounds of the invention are named according to systematic applicationof the nomenclature rules agreed upon by the International Union of Pureand Applied Chemistry (IUPAC), International Union of Biochemistry andMolecular Biology (IUBMB), and the Chemical Abstracts Service (CAS).

The compounds of the invention, or their pharmaceutically acceptablesalts, may have asymmetric carbon atoms, oxidized sulfur atoms orquaternized nitrogen atoms in their structure.

The compounds of the invention and their pharmaceutically acceptablesalts may exist as single stereoisomers, racemates, and as mixtures ofenantiomers and diastereomers. The compounds may also exist as geometricisomers. All such single stereoisomers, racemates and mixtures thereof,and geometric isomers are intended to be within the scope of thisinvention.

It is assumed that when considering generic descriptions of compounds ofthe invention for the purpose of constructing a compound, suchconstruction results in the creation of a stable structure. That is, oneof ordinary skill in the art would recognize that there cantheoretically be some constructs which would not normally be consideredas stable compounds (that is, sterically practical and/or syntheticallyfeasible, supra).

When a particular group with its bonding structure is denoted as beingbonded to two partners; that is, a divalent group, for example, —OCH₂—,then it is understood that either of the two partners may be bound tothe particular group at one end, and the other partner is necessarilybound to the other end of the particular group, unless stated explicitlyotherwise. Stated another way, divalent groups are not to be construedas limited to the depicted orientation, for example “—OCH₂—” is meant tomean not only “—OCH₂—” as drawn, but also “—CH₂O—.

In addition to the preferred embodiments recited hereinabove, alsopreferred are embodiments comprising combinations of preferredembodiments.

Methods for the preparation and/or separation and isolation of singlestereoisomers from racemic mixtures or non-racemic mixtures ofstereoisomers are well known in the art. For example, optically active(R)- and (S)-isomers may be prepared using chiral synthons or chiralreagents, or resolved using conventional techniques. Enantiomers (R- andS-isomers) may be resolved by methods known to one of ordinary skill inthe art, for example by: formation of diastereoisomeric salts orcomplexes which may be separated, for example, by crystallization; viaformation of diastereoisomeric derivatives which may be separated, forexample, by crystallization, selective reaction of one enantiomer withan enantiomer-specific reagent, for example enzymatic oxidation orreduction, followed by separation of the modified and urunodifiedenantiomers; or gas-liquid or liquid chromatography in a chiralenvironment, for example on a chiral support, such as silica with abound chiral ligand or in the presence of a chiral solvent. It will beappreciated that where a desired enantiomer is converted into anotherchemical entity by one of the separation procedures described above, afurther step may be required to liberate the desired enantiomeric form.Alternatively, a specific enantiomer may be synthesized by asymmetricsynthesis using optically active reagents, substrates, catalysts orsolvents or by converting on enantiomer to the other by asymmetrictransformation. For a mixture of enantiomers, enriched in a particularenantiomer, the major component enantiomer may be further enriched (withconcomitant loss in yield) by recrystallization.

“Patient” for the purposes of the present invention includes humans andother animals, particularly mammals, and other organisms. Thus themethods are applicable to both human therapy and veterinaryapplications. In a preferred embodiment the patient is a mammal, and ina most preferred embodiment the patient is human.

“Kinase-dependent diseases or conditions” refer to pathologic conditionsthat depend on the activity of one or more protein kinases. Kinaseseither directly or indirectly participate in the signal transductionpathways of a variety of cellular activities including proliferation,adhesion, migration, differentiation and invasion. Diseases associatedwith kinase activities include tumor growth, the pathologicneovascularization that supports solid tumor growth, and associated withother diseases where excessive local vascularization is involved such asocular diseases (diabetic retinopathy, age-related macular degeneration,and the like) and inflammation (psoriasis, rheumatoid arthritis, and thelike).

While not wishing to be bound to theory, phosphatases can also play arole in “kinase-dependent diseases or conditions” as cognates ofkinases; that is, kinases phosphorylate and phosphatasesdephosphorylate, for example protein substrates. Therefore compounds ofthe invention, while modulating kinase activity as described herein, mayalso modulate, either directly or indirectly, phosphatase activity. Thisadditional modulation, if present, may be synergistic (or not) toactivity of compounds of the invention toward a related or otherwiseinterdependent kinase or kinase family. In any case, as statedpreviously, the compounds of the invention are useful for treatingdiseases characterized in part by abnormal levels of cell proliferation(i.e. tumor growth), programmed cell death (apoptosis), cell migrationand invasion and angiogenesis associated with tumor growth.

“Therapeutically effective amount” is an amount of a compound of theinvention, that when administered to a patient, ameliorates a symptom ofthe disease. The amount of a compound of the invention which constitutesa “therapeutically effective amount” will vary depending on thecompound, the disease state and its severity, the age of the patient tobe treated, and the like. The therapeutically effective amount can bedetermined routinely by one of ordinary skill in the art having regardto their knowledge and to this disclosure.

“Cancer” refers to cellular-proliferative disease states, including butnot limited to: Cardiac: sarcoma (angiosarcoma, fibrosarcoma,rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma andteratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiatedsmall cell, undifferentiated large cell, adenocarcinoma), alveolar(bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma,chondromatous hanlartoma, inesothelioma; Gastrointestinal: esophagus(squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma),stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductaladenocarcinoma, insulinorna, glucagonoma, gastrinoma, carcinoid tumors,vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors,Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma,fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma,hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma,Wilm's tumor [nephroblastoma], lymphoma, leukemia), bladder and urethra(squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma),prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma,embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma,interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors,lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma,hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bone:osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibroushistiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma(reticulum cell sarcoma), multiple myeloma, malignant giant cell tumorchordoma, osteochronfroma (osteocartilaginous exostoses), benignchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma andgiant cell tumors; Nervous system: skull (osteoma, hemangioma,granuloma, xanthoma, osteitis defornians), meninges (meningioma,meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma,glioma, ependymoma, germinoma [pinealoma], glioblastoma multiform,oligodendroglioma, schwannoma, retinoblastoma, congenital tumors),spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological:uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumorcervical dysplasia), ovaries (ovarian carcinoma [serouscystadenocarcinoma, mucinous cystadenocarcinoma, unclassifiedcarcinoma], granulosa-thecal cell tumors, Sertoli-Leydig cell tumors,dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma,intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma),vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma(embryonal rhabdomyosarcoma], fallopian tubes (carcinoma); Hematologic:blood (myeloid leukemia [acute and chronic], acute lymphoblasticleukemia, chronic lymphocytic leukemia, myeloproliferative diseases,multiple myeloma, myelodysplastic syndrome), Hodgkin's disease,non-Hodgkin's lymphoma [malignant lymphoma); Skin: malignant melanoma,basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, molesdysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis;Adrenal Glands: neuroblastoma; and breast cancer. Thus, the term“cancerous cell” as provided herein, includes a cell afflicted by anyone of the above-identified conditions.

“Pharmaceutically acceptable acid addition salt” refers to those saltsthat retain the biological effectiveness of the free bases and that arenot biologically or otherwise undesirable, formed with inorganic acidssuch as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like, as well as organic acids such as aceticacid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid,oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid and the like.

“Pharmaceutically acceptable base addition salts” include those derivedfrom inorganic bases such as sodium, potassium, lithium, ammonium,calcium, magnesium, iron, zinc, copper, manganese, aluminum salts andthe like. Exemplary salts are the ammonium, potassium, sodium, calcium,and magnesium salts. Salts derived from pharmaceutically acceptableorganic non-toxic bases include, but are not limited to, salts ofprimary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines and basic ionexchange resins, such as isopropylamine, trimethylamine, diethylamine,triethylarnine, tripropylamine, ethanolamine, 2-dimethylaminoethanol,2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine,caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine,glucosamine, methylglucamine, theobromine, purines, piperazine,piperidine, N-ethylpiperidine, polyamine resins, and the like. Exemplaryorganic bases are isopropylamine, diethylamine, ethanolamine,trimethylanine, dicyclohexylamine, choline, and caffeine. (See, forexample, S. M. Berge, et al., “Pharmaceutical Salts,” J. Pharm. Sci.,1977;66:1-19 which is incorporated herein by reference.).

“Metabolite” refers to the break-down or end product of a compound orits salt produced by metabolism or biotransformation in the animal orhuman body; for example, biotransformation to a more polar molecule suchas by oxidation, reduction, or hydrolysis, or to a conjugate (seeGoodman and Gilman, “The Pharmacological Basis of Therapeutics” 8.sup.thEd., Pergamon Press, Gilman et al. (eds), 1990 for a discussion ofbiotransformation). As used herein, the metabolite of a compound of theinvention or its salt may be the biologically active form of thecompound in the body. In one example, a prodrug may be used such thatthe biologically active form, a metabolite, is released in vivo. Inanother example, a biologically active metabolite is discoveredserendipitously, that is, no prodrug design per se was undertaken. Anassay for activity of a metabolite of a compound of the presentinvention is known to one of skill in the art in light of the presentdisclosure.

In addition, the compounds of the present invention can exist inunsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. In general, the solvatedforms are considered equivalent to the unsolvated forms for the purposesof the present invention.

In addition, it is intended that the present invention cover compoundsmade either using standard organic synthetic techniques, includingcombinatorial chemistry or by biological methods, such as bacterialdigestion, metabolism, enzymatic conversion, and the like.

“Treating” or “treatment” as used herein covers the treatment of adisease-state in a human, which disease-state is characterized byabnormal cellular proliferation, and invasion and includes at least oneof: (i) preventing the disease-state from occurring in a human, inparticular, when such human is predisposed to the disease-state but hasnot yet been diagnosed as having it; (ii) inhibiting the disease-state,i.e., arresting its development; and (iii) relieving the disease-state,i.e., causing regression of the disease-state. As is known in the art,adjustments for systemic versus localized delivery, age, body weight,general health, sex, diet, time of administration, drug interaction andthe severity of the condition may be necessary, and will beascertainable with routine experimentation by one of ordinary skill inthe art.

One of ordinary skill in the art would understand that certaincrystallized, protein-ligand complexes, in particular IRK, IGF1R, c-Met,c-Kit, KDR, flt-3, or flt-4-ligand complexes, and their correspondingx-ray structure coordinates can be used to reveal new structuralinformation useful for understanding the biological activity of kinasesas described herein. As well, the key structural features of theaforementioned proteins, particularly, the shape of the ligand bindingsite, are useful in methods for designing or identifying selectivemodulators of kinases and in solving the structures of other proteinswith similar features. Such protein-ligand complexes, having compoundsof the invention as their ligand component, are an embodiment of theinvention.

As well, one of ordinary skill in the art would appreciate that suchsuitable x-ray quality crystals can be used as part of a method ofidentifying a candidate agent capable of binding to and modulating theactivity of kinases. Such methods may be characterized by the followingembodiments: a) introducing into a suitable computer program,information defining a ligand binding domain of a kinase in aconformation (e.g. as defined by x-ray structure coordinates obtainedfrom suitable x-ray quality crystals as described above) wherein thecomputer program creates a model of the three dimensional structures ofthe ligand binding domain, b) introducing a model of the threedimensional structure of a candidate agent in the computer program, c)superimposing the model of the candidate agent on the model of theligand binding domain, and d) assessing whether the candidate agentmodel fits spatially into the ligand binding domain. Embodiments a-d arenot necessarily carried out in the aforementioned order. Such methodsmay further entail: performing rational drug design with the model ofthe three-dimensional structure, and selecting a potential candidateagent in conjunction with computer modeling.

Additionally, one skilled in the art would appreciate that such methodsmay further entail: employing a candidate agent, so-determined to fitspatially into the ligand binding domain, in a biological activity assayfor kinase modulation, and determining whether said candidate agentmodulates kinase activity in the assay. Such methods may also includeadministering the candidate agent, determined to modulate kinaseactivity, to a mammal suffering from a condition treatable by kinasemodulation, such as those described above.

Also, one skilled in the art would appreciate that compounds of theinvention can be used in a method of evaluating the ability of a testagent to associate with a molecule or molecular complex comprising aligand binding domain of a kinase. Such a method may be characterized bythe following embodiments: a) creating a computer model of a kinasebinding pocket using structure coordinates obtained from suitable x-rayquality crystals of the kinase, b) employing computational algorithms toperform a fitting operation between the test agent and the computermodel of the binding pocket, and c) analyzing the results of the fittingoperation to quantify the association between the test agent and thecomputer model of the binding pocket.

General Administration

Administration of the compounds of the invention, or theirpharmaceutically acceptable salts, in pure form or in an appropriatepharmaceutical composition, can be carried out via any of the acceptedmodes of administration or agents for serving similar utilities. Thus,administration can be, for example, orally, nasally, parenterally(intravenous, intramuscular, or subcutaneous), topically,transderrnally, intravaginally, intravesically, intracistemally, orrectally, in the form of solid, semi-solid, lyophilized powder, orliquid dosage forms, such as for example, tablets, suppositories, pills,soft elastic and hard gelatin capsules, powders, solutions, suspensions,or aerosols, or the like, preferably in unit dosage forms suitable forsimple administration of precise dosages.

The compositions will include a conventional pharmaceutical carrier orexcipient and a compound of the invention as the/an active agent, and,in addition, may include other medicinal agents, pharmaceutical agents,carriers, adjuvants, etc. Compositions of the invention may be used incombination with anticancer or other agents that are generallyadministered to a patient being treated for cancer. Adjuvants includepreserving, wetting, suspending, sweetening, flavoring, perfuming,emulsifying, and dispensing agents. Prevention of the action ofmicroorganisms can be ensured by various antibacterial and antifungalagents, for example, parabens, chlorobutanol, phenol, sorbic acid, andthe like. It may also be desirable to include isotonic agents, forexample sugars, sodium chloride, and the like. Prolonged absorption ofthe injectable pharmaceutical form can be brought about by the use ofagents delaying absorption, for example, aluminum monostearate andgelatin.

If desired, a pharmaceutical composition of the invention may alsocontain minor amounts of auxiliary substances such as wetting oremulsifying agents, pH buffering agents, antioxidants, and the like,such as, for example, citric acid, sorbitan monolaurate, triethanolamineoleate, butylalted hydroxytoluene, etc.

Compositions suitable for parenteral injection may comprisephysiologically acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions or emulsions, and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and nonaqueous carriers, diluents, solventsor vehicles include water, ethanol, polyols (propyleneglycol,polyethyleneglycol, glycerol, and the like), suitable mixtures thereof,vegetable oils (such as olive oil) and injectable organic esters such asethyl oleate. Proper fluidity can be maintained, for example, by the useof a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersions and by the use of surfactants.

One preferable route of administration is oral, using a convenient dailydosage regimen that can be adjusted according to the degree of severityof the disease-state to be treated.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is admixed with at least one inert customary excipient (orcarrier) such as sodium citrate or dicalcium phosphate or (a) fillers orextenders, as for example, starches, lactose, sucrose, glucose,mannitol, and silicic acid, (b) binders, as for example, cellulosederivatives, starch, alignates, gelatin, polyvinylpyrrolidone, sucrose,and gum acacia, (c) humectants, as for example, glycerol, (d)disintegrating agents, as for example, agar-agar, calcium carbonate,potato or tapioca starch, alginic acid, croscarmellose sodium, complexsilicates, and sodium carbonate, (e) solution retarders, as for exampleparaffin, (f) absorption accelerators, as for example, quaternaryammonium compounds, (g) wetting agents, as for example, cetyl alcohol,and glycerol monostearate, magnesium stearate and the like (h)adsorbents, as for example, kaolin and bentonite, and (i) lubricants, asfor example, talc, calcium stearate, magnesium stearate, solidpolyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In thecase of capsules, tablets, and pills, the dosage forms may also comprisebuffering agents.

Solid dosage forms as described above can be prepared with coatings andshells, such as enteric coatings and others well known in the art. Theymay contain pacifying agents, and can also be of such composition thatthey release the active compound or compounds in a certain part of theintestinal tract in a delayed manner. Examples of embedded compositionsthat can be used are polymeric substances and waxes. The activecompounds can also be in microencapsulated form, if appropriate, withone or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirs. Suchdosage forms are prepared, for example, by dissolving, dispersing, etc.,a compound(s) of the invention, or a pharmaceutically acceptable saltthereof, and optional pharmaceutical adjuvants in a carrier, such as,for example, water, saline, aqueous dextrose, glycerol, ethanol and thelike; solubilizing agents and emulsifiers, as for example, ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol,dimethylformamide; oils, in particular, cottonseed oil, groundnut oil,corn germ oil, olive oil, castor oil and sesame oil, glycerol,tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters ofsorbitan; or mixtures of these substances, and the like, to thereby forma solution or suspension.

Suspensions, in addition to the active compounds, may contain suspendingagents, as for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, or mixtures of thesesubstances, and the like.

Compositions for rectal administrations are, for example, suppositoriesthat can be prepared by mixing the compounds of the present inventionwith for example suitable non-irritating excipients or carriers such ascocoa butter, polyethyleneglycol or a suppository wax, which are solidat ordinary temperatures but liquid at body temperature and therefore,melt while in a suitable body cavity and release the active componenttherein.

Dosage forms for topical administration of a compound of this inventioninclude ointments, powders, sprays, and inhalants. The active componentis admixed under sterile conditions with a physiologically acceptablecarrier and any preservatives, buffers, or propellants as may berequired. Ophthalmic Formulations, eye ointments, powders, and solutionsare also contemplated as being within the scope of this invention.

Generally, depending on the intended mode of administration, thepharmaceutically acceptable compositions will contain about 1% to about99% by weight of a compound(s) of the invention, or a pharmaceuticallyacceptable salt thereof, and 99% to 1% by weight of a suitablepharmaceutical excipient. In one example, the composition will bebetween about 5% and about 75% by weight of a compound(s) of theinvention, or a pharmaceutically acceptable salt thereof, with the restbeing suitable pharmaceutical excipients.

Actual methods of preparing such dosage forms are known, or will beapparent, to those skilled in this art; for example, see Remington'sPharmaceutical Sciences, 18th Ed., (Mack Publishing Company, Easton,Pa., 1990). The composition to be administered will, in any event,contain a therapeutically effective amount of a compound of theinvention, or a pharmaceutically acceptable salt thereof, for treatmentof a disease-state in accordance with the teachings of this invention.

The compounds of the invention, or their pharmaceutically acceptablesalts, are administered in a therapeutically effective amount which willvary depending upon a variety of factors including the activity of thespecific compound employed, the metabolic stability and length of actionof the compound, the age, body weight, general health, sex, diet, modeand time of administration, rate of excretion, drug combination, theseverity of the particular disease-states, and the host undergoingtherapy. The compounds of the present invention can be administered to apatient at dosage levels in the range of about 0.1 to about 1,000 mg perday. For a normal human adult having a body weight of about 70kilograms, a dosage in the range of about 0.01 to about 100 mg perkilogram of body weight per day is an example. The specific dosage used,however, can vary. For example, the dosage can depend on a number offactors including the requirements of the patient, the severity of thecondition being treated, and the pharmacological activity of thecompound being used. The determination of optimum dosages for aparticular patient is well known to one of ordinary skill in the art.

General Synthetic Section

The compounds of the invention, or their pharmaceutically acceptablesalts, may have asymmetric carbon atoms or quaternized nitrogen atoms intheir structure.

It is assumed that when considering generic descriptions of compounds ofthe invention for the purpose of constructing a compound, suchconstruction results in the creation of a stable structure. That is, oneof ordinary skill in the art would recognize that theoretically someconstructs which would not normally be considered as stable compounds(that is, sterically practical and/or synthetically feasible, supra).

The compounds of the invention and their pharmaceutically acceptablesalts may exist as single stereoisomers, racemates, and as mixtures ofenantiomers and diastereomers. The compounds may also exist as geometricisomers. All such single stereoisomers, racemates and mixtures thereof,and geometric isomers are intended to be within the scope of thisinvention.

Methods for the preparation and/or separation and isolation of singlestereoisomers from racemic mixtures or non-racemic mixtures ofstereoisomers are well known in the art. For example, optically active(R)- and (S)-isomers may be prepared using chiral synthons or chiralreagents, or resolved using conventional techniques. Enantiomers (R- andS-isomers) may be resolved by methods known to one of ordinary skill inthe art, for example by: formation of diastereoisomeric salts orcomplexes which may be separated, for example, by crystallization; viaformation of diastereoisomeric derivatives which may be separated, forexample, by crystallization, selective reaction of one enantiomer withan enantiomer-specific reagent, for example enzymatic oxidation orreduction, followed by separation of the modified and unmodifiedenantiomers; or gas-liquid or liquid chromatography in a chiralenvironment, for example on a chiral support, such as silica with abound chiral ligand or in the presence of a chiral solvent. It will beappreciated that where a desired enantiomer is converted into anotherchemical entity by one of the separation procedures described above, afurther step may be required to liberate the desired enantiomeric form.Alternatively, specific enantiomer may be synthesized by asymmetricsynthesis using optically active reagents, substrates, catalysts orsolvents or by converting on enantiomer to the other by asymmetrictransformation. For a mixture of enantiomers, enriched in a particularenantiomer, the major component enantiomer may be further enriched (withconcomitant loss in yield) by recrystallization.

In addition, the compounds of the present invention can exist inunsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. In general, the solvatedforms are considered equivalent to the unsolvated forms for the purposesof the present invention.

In addition, it is intended that the present invention cover compoundsmade either using standard organic synthetic techniques, includingcombinatorial chemistry or by biological methods, such as bacterialdigestion, metabolism, enzymatic conversion, and the like.

Abbreviations and their Definitions

The following abbreviations and terms have the indicated meaningsthroughout:

Abbreviation Meaning Ac acetyl br broad ° C. degrees Celsius c- cycloCBZ CarboBenZoxy = benzyloxycarbonyl d doublet dd doublet of doublet dtdoublet of triplet DIPEA N,N-diisopropylethylamine DMFN,N-dimethylformamide DMSO dimethyl sulfoxide EI Electron Impactionization Et Ethyl g gram(s) GC gas chromatography h or hr hour(s) HOAcacetic acid HOBt Hydroxybenzotriazole HPLC high pressure liquidchromatography L liter(s) M molar or molarity m Multiplet Me Methylmesyl Methanesulfonyl mg milligram(s) MHz megahertz (frequency) Minminute(s) mL milliliter(s) mM Millimolar mmol millimole(s) mol mole(s)MS mass spectral analysis MTBE methyl t-butyl ether N normal ornormality NBS N-bromosuccinimide NCS N-chlorosuccinimide nM NanomolarNMO N-methylmorpholine oxide NMR nuclear magnetic resonance spectroscopyPEG polyethylene glycol pEY poly-glutamine, tyrosine Ph Phenyl PhOHPhenol PfP Pentafluorophenol PfPy Pentafluoropyridine PPTS Pyridiniump-toluenesulfonate Py Pyridine PyBroP bromo-tris-pyrrolidino-phosphoniumhexafluorophosphate q Quartet RT Room temperature Sat'd Saturated sSinglet s- Secondary t- Tertiary t or tr Triplet TBDMSt-butyldimethylsilyl TES Triethylsilyl TFA trifluoroacetic acid THFTetrahydrofuran TMOF trimethyl orthoformate TMS trimethylsilyl tosylp-toluenesulfonyl Trt triphenylmethyl uL microliter(s) uM Micromole(s)or micromolar

Section I

As noted above, this invention relates to compounds of Formula I andwhich inhibit MEK.

In one embodiment, in section I the invention provides a compound ofFormula I below:

-   and optionally a pharmaceutically acceptable salt or solvate    thereof, wherein the A ring represents an arylene or heteroarylene    group and the A ring is optionally substituted with one, two, three    or four groups selected from R¹⁰, R¹², R¹⁴, and R¹⁶ where R¹⁰, R¹²,    R¹⁴, and R¹⁶ are independently hydrogen, lower alkanyl, lower    alkenyl, lower alkynyl, halo, haloalkoxy, hydroxy, lower alkoxy,    amino, alkylamino, dialkylamino, haloalkyl, —NHS(O)₂R⁸, —CN,    —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′) or —NR⁸C(O)R^(8′);-   X is lower alkyl, halo, haloalkyl, or haloalkoxy;-   R¹, R², R³, R⁴, R⁵ and R⁶ are independently hydrogen, halo, nitro,    —NR⁸R^(8′), —OR⁸, —NHS(O)₂R⁸, —CN, —S(O)_(m)R⁸, —S(O)₂NR⁸R^(8′),    —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′), —NR⁸C(O)OR^(8′),    —NR⁸C(O)NR^(8′)R^(8′), —NR⁸C(O)OR^(8′), or —NR⁸C(O)R^(8′);-   R¹, R², R³, R⁴, R⁵ and R⁶ are independently lower alkanyl, lower    alkenyl, lower alkynyl, cycloalkyl, heteroaryl, or heterocycloalkyl;    where the lower alkanyl, lower alkenyl, lower alkynyl, cycloalkyl,    heteroaryl, and heterocycloalkyl are optionally substituted with    one, two, three, four, five, six or seven groups independently    selected from halo, lower alkanyl, haloalkyl, nitro, optionally    substituted cycloalkyl, optionally substituted heterocycloalkyl,    optionally substituted aryl, optionally substituted arylalkyl,    optionally substituted heteroaryl, —OR⁸, —NR⁸R^(8′), —NHS(O)₂R⁸,    —CN, —S(O)_(m)R⁸, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′),    —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′), and —NR⁸C(O)R^(8′), or-   one of R¹ and R² together with the carbon to which they are    attached, R³ and R⁴ together with the carbon to which they are    attached, and R⁵ and R⁶ together with the carbon to which they are    attached form C(O) or C(═NOH);-   m is 1 or 2;-   R⁷ is hydrogen, halo or lower alkyl; and-   R⁸, R^(8′) and R^(8″) are independently hydrogen, hydroxy, alkoxy,    substituted alkoxy, lower alkanyl, haloalkyl, lower alkenyl, lower    alkynyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl; where    the lower alkanyl, lower alkenyl, lower alkynyl, aryl, cycloalkyl,    heteroaryl, and heterocycloalkyl are independently optionally    substituted with one, two three, four, or five groups independently    selected from lower alkanyl, halo, hydroxy, hydroxyalkyl, lower    alkoxy, substituted alkoxy, alkoxyalkyl, haloalkyl, carboxy, carboxy    ester, nitro, cyano, —S(O)_(n)R³¹ (where n is 0, 1, or 2 and R³¹ is    alkyl, substituted alkyl, optionally substituted aryl, optionally    substituted heterocycloalkyl, or optionally substituted heteroaryl),    —NR³⁴SO₂R^(34a) (where R³⁴ is hydrogen or lower alkyl and R^(34a) is    lower alkyl, lower alkenyl, optionally substituted aryl, optionally    substituted heterocycloalkyl, optionally substituted cycloalkyl, or    optionally substituted heteroaryl), —SO₂NR³⁵R^(35a) (where R³⁵ is    hydrogen or alkyl and R^(35a) is lower alkyl, lower alkenyl,    optionally substituted aryl,optionally substituted heterocycloalkyl,    optionally substituted cycloalkyl, or optionally substituted    heteroaryl), optionally substituted cycloalkyl, optionally    substituted heterocycloalkyl, optionally substituted aryl,    optionally substituted arylalkyl, aryloxy, arylalkyloxy, optionally    substituted heteroaryl, —NHC(O)R³² (where R³² is lower alkanyl,    lower alkenyl, alkoxy, or cycloalkyl) and —NR³⁰R^(30′) (where R³⁰    and R^(30′) are independently hydrogen, lower alkyl, or    hydroxyalkyl), and —C(O)NHR³³ (where R³³ is lower alkanyl, lower    alkenyl, lower alkynyl, or cycloalkyl).

In one embodiment, in section I the invention provides a compound ofFormula Ia below:

and optionally as a pharmaceutically acceptable salt or solvate thereof,wherein

-   the A ring represents an arylene or heteroarylene group and the A    ring is optionally substituted with one, two, three or four groups    selected from R¹⁰, R¹², R¹⁴, and R¹⁶ where R¹⁰, R¹², R¹⁴, and R¹⁶    are independently hydrogen, lower alkanyl, lower alkenyl, lower    alkynyl, halo, haloalkoxy, hydroxy, lower alkoxy, amino, alkylamino,    dialkylamino, haloalkyl, —NHS(O)₂R⁸, —CN, —C(O)R⁸, —C(O)OR⁸,    —C(O)NR⁸R^(8′) or —NR⁸C(O)R^(8′);-   X is lower alkyl, halo, haloalkyl, or haloalkoxy;-   R¹, R², R³, R⁴, R⁵ and R⁶ are independently hydrogen, halo, nitro,    —NR⁸R^(8′), —OR⁸, —NHS(O)₂R⁸, —CN, —S(O)_(m)R⁸, —S(O)₂NR⁸R^(8′),    —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′), —NR⁸C(O)OR^(8′),    —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′), —NR⁸C(O)R^(8′), lower    alkanyl, lower alkenyl, lower alkynyl, cycloalkyl, heteroaryl, or    heterocycloalkyl; where the lower alkanyl, lower alkenyl, lower    alkynyl, cycloalkyl, heteroaryl, and heterocycloalkyl are optionally    substituted with one, two, three, four, five, six or seven groups    independently selected from halo, lower alkanyl, haloalkyl, nitro,    optionally substituted cycloalkyl, optionally substituted    heterocycloalkyl, optionally substituted aryl, optionally    substituted arylalkyl, optionally substituted heteroaryl, —OR⁸,    —NR⁸R^(8′), —NHS(O)₂R⁹, —CN, —S(O)_(m)R⁹, —C(O)R⁸, —C(O)OR⁸,    —C(O)NR⁸R^(8′), —NR⁸C(O)NR⁸R^(8″), —NR⁸C(O)OR^(8′), and    —NR⁸C(O)R^(8′); or-   one of R¹ and R² together with the carbon to which they are    attached, R³ and R⁴ together with the carbon to which they are    attached, and R⁵ and R⁶ together with the carbon to which they are    attached form C(O) or C(═NOH);-   m is 1 or 2;-   R⁷ is hydrogen, halo or lower alkyl;-   R⁸, R^(8′) and R^(8″) are independently hydrogen, hydroxy, alkoxy,    substituted alkoxy, lower alkanyl, haloalkyl, lower alkenyl, lower    alkynyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl; where    the lower alkanyl, lower alkenyl, lower alkynyl, aryl, cycloalkyl,    heteroaryl, and heterocycloalkyl are independently optionally    substituted with one, two three, four, or five groups independently    selected from lower alkanyl, halo, hydroxy, hydroxyalkyl, lower    alkoxy, substituted alkoxy, alkoxyalkyl, haloalkyl, carboxy, carboxy    ester, nitro, cyano, —S(O)_(n)R³¹ (where n is 0, 1, or 2 and R³¹ is    alkyl, substituted alkyl, optionally substituted aryl, optionally    substituted heterocycloalkyl, or optionally substituted heteroaryl),    —NR³⁴SO₂R^(34a) (where R³⁴ is hydrogen or lower alkyl and R^(34a) is    lower alkyl, lower alkenyl, optionally substituted aryl, optionally    substituted heterocycloalkyl, optionally substituted cycloalkyl, or    optionally substituted heteroaryl), —SO₂NR³⁵R^(35a) (where R³⁵ is    hydrogen or alkyl and R^(35a) is lower alkyl, lower alkenyl,    optionally substituted aryl,optionally substituted heterocycloalkyl,    optionally substituted cycloalkyl, or optionally substituted    heteroaryl), optionally substituted cycloalkyl, optionally    substituted heterocycloalkyl, optionally substituted aryl,    optionally substituted arylalkyl, aryloxy, arylalkyloxy, optionally    substituted heteroaryl, —NHC(O)R³² (where R³² is lower alkanyl,    lower alkenyl, alkoxy, or cycloalkyl) and —NR³⁰R^(30′) (where R³⁰    and R^(30′) are independently hydrogen, lower alkyl, or    hydroxyalkyl), and —C(O)NHR³³ (where R³³ is lower alkanyl, lower    alkenyl, lower alkynyl, or cycloalkyl); and-   R⁹ is lower alkanyl, lower alkenyl, lower alkynyl, aryl, cycloalkyl,    heteroaryl, or heterocycloalkyl; where the lower alkanyl, lower    alkenyl, lower alkynyl, aryl, cycloalkyl, heteroaryl, and    heterocycloalkyl are independently optionally substituted with one,    two, three, four, or five groups selected from lower alkanyl, halo,    hydroxy, haloalkoxy, haloalkyl, amino, alkylamino, and dialkylamino.

In another embodiment, the invention provides a compound of Formula I orIa where R⁷ is halo and all other groups are as defined for a Compoundof Formula I or Ia, respectively. In another embodiment, R⁷ is iodo orbromo. In another embodiment, R⁷ is iodo. In another embodiment, thecompound is that where R⁷ is iodo or bromo; the A ring is phenyleneoptionally substituted with one, two, three, or four groups selectedfrom R¹⁰, R¹², R¹⁴, and R¹⁶; and all other groups are as defined for aCompound of Formula I or Ia, respectively.

In another embodiment, the invention provides a compound of Formula I orIa where X is halo and all other groups are as defined for a Compound ofFormula I or Ia, respectively. In another embodiment, X is fluoro orchloro. In another embodiment, X is fluoro. In yet another embodiment,the compound is that where X is fluoro or chloro; the A ring isphenylene optionally substituted with one, two, three, or four groupsselected from R¹⁰, R¹², R¹⁴, and R¹⁶; and all other groups are asdefined for a Compound of Formula I or Ia, respectively.

In another embodiment, the invention provides a compound of Formula I orIa where R¹, R², R⁵, and R⁶ are hydrogen and all other groups are asdefined for a Compound of Formula I or Ia, respectively. In anotherembodiment, R¹, R², R⁵, and R⁶ are hydrogen; the A ring is phenyleneoptionally substituted with one, two, three, or four groups selectedfrom R¹⁰, R¹², R¹⁴, and R¹⁶; and all other groups are as defined for aCompound of Formula I or Ia, respectively.

In another embodiment, the invention provides a compound of Formula I orIa where the A ring is a phenylene ring optionally substituted with one,two, three, or four groups selected from R¹⁰, R¹², R¹⁴, and R¹⁶ whereR¹⁰, R¹², R¹⁴, R¹⁶, and all groups are as defined for a Compound ofFormula I or Ia, respectively.

In another embodiment, the invention provides a compound of Formula I orIa where R⁷ and X are halo and all other groups are as defined for aCompound of Formula I or Ia, respectively. In another embodiment, R⁷ isiodo and X is fluoro.

In yet another embodiment (A1), the compound of Formula I or Ia is thatwhere R⁷ and X are halo; the A ring is phenylene optionally substitutedwith one, two, three, or four groups selected from R¹⁰, R¹², R¹⁴, andR¹⁶; and all other groups are as defined for a Compound of Formula I orIa, respectively. In another embodiment, R⁷ is iodo and X is fluoro; theA ring is phenylene optionally substituted with one, two, three, or fourgroups selected from R¹⁰, R¹², R¹⁴, and R¹⁶; and all other groups are asdefined for a Compound of Formula I or Ia, respectively.

In another embodiment (A2), the invention provides a Compound of FormulaI or Ia where the A ring is phenylene; R¹⁴ and R¹⁶ are hydrogen; R¹⁰ andR¹² are independently hydrogen or halo; and all other groups are asdefined for a Compound of Formula I or Ia, respectively In anotherembodiment, R¹⁰ and R¹² are independently hydrogen or fluoro. In anotherembodiment, R¹⁰ is 3-fluoro and R¹² is hydrogen. In another embodiment,R¹⁰ and R¹² are fluoro. In another embodiment, R¹⁰ and R¹² are 3-fluoroand 4-fluoro, 4-fluoro and 5-fluoro, or 4-fluoro and 6-fluoro.

In another embodiment of the invention (A3), the compound of Formula Ior Ia is that where R¹, R², R⁵ and R⁶ are hydrogen; the A ring isphenylene optionally substituted with one, two, three, or four groupsselected from R¹⁰, R¹², R¹⁴, and R¹⁶; and all other groups are asdefined for a Compound of Formula I or Ia, respectively.

In another embodiment (A4), the invention provides a Compound of FormulaIa where the A ring is phenylene optionally substituted with one, two,three, or four groups selected from R¹⁰, R¹², R¹⁴, and R¹⁶; X, R⁷, R¹⁰,R¹², R¹⁴, and R¹⁶ are as defined for a Compound of Formula Ia; and

-   one of R¹, R², R³, R⁴, R⁵, and R⁶ is halo, nitro, —NR⁸R^(8′), —OR⁸,    —NHS(O)₂R⁸, —CN, —S(O)_(m)R⁸, —S(O)₂NR⁸R^(8′), —C(O)R⁸, —C(O)OR⁸,    —C(O)NR⁸R^(8′), —NR⁸C(O)OR^(8′), —NR⁸C(O)NR^(8′)R^(8″),    —NR⁸C(O)OR^(8′), —NR⁸C(O)R^(8′), lower alkanyl, lower alkenyl, lower    alkynyl, cycloalkyl, heteroaryl, or heterocycloalkyl; where the    lower alkanyl, lower alkenyl, lower alkynyl, cycloalkyl, heteroaryl,    and heterocycloalkyl are independently optionally substituted with    one, two, three, four, five, six or seven groups independently    selected from halo, lower alkanyl, haloalkyl, nitro, optionally    substituted cycloalkyl, optionally substituted heterocycloalkyl,    optionally substituted aryl, optionally substituted arylalkyl,    optionally substituted heteroaryl, —OR⁸, —NR⁸R^(8′), —NHS(O)₂R⁹,    —CN, —S(O)_(m)R⁹, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′),    —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′) and —NR⁸C(O)R^(8′); and the    others of R¹, R², R³, R⁴, R⁵, and R⁶ are as defined for a Compound    of Formula Ia; or-   one of R¹ and R² together with the carbon to which they are    attached, R³ and R⁴ together with the carbon to which they are    attached, and R⁵ and R⁶ together with the carbon to which they are    attached forms C(O) or C(═NOH); the others of R¹, R², R³, R⁴, R⁵,    and R⁶ are as defined for a Compound of Formula Ia; and    all other groups are as defined in Formula Ia.

In another embodiment (A5), the invention provides a Compound of FormulaIa where the A ring is phenylene optionally substituted with one, two,three, or four groups selected from R¹⁰, R¹², R¹⁴, and R¹⁶; X, R⁷, R¹⁰,R¹², R¹⁴, and R¹⁶ are as defined for a Compound of Formula Ia; and

-   R³ is halo, nitro, —NR⁸R^(8′), —OR⁸, —NHS(O)₂R⁸, —CN, —S(O)_(m)R⁸,    —S(O)₂NR⁸R^(8′), —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′), —NR⁸C(O)OR^(8′),    —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′), —NR⁸C(O)R^(8′), lower    alkanyl, lower alkenyl, lower alkynyl, cycloalkyl, heteroaryl, or    heterocycloalkyl; where the lower alkanyl, lower alkenyl, lower    alkynyl, cycloalkyl, heteroaryl, and heterocycloalkyl are    independently optionally substituted with one, two, three, four,    five, six or seven groups independently selected from halo, lower    alkanyl, haloalkyl, nitro, optionally substituted cycloalkyl,    optionally substituted heterocycloalkyl, optionally substituted    aryl, optionally substituted arylalkyl, optionally substituted    heteroaryl, —OR⁸, —NR⁸R^(8′), —NHS(O)₂R⁹, —CN, —S(O)_(m)R⁹, —C(O)R⁸,    —C(O)OR⁸, —C(O)NR⁸R^(8′), —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′) and    —NR⁸C(O)R^(8′); and R⁴ is as defined in Formula Ia; or    R³ and R⁴ together with the carbon to which they are attached form    C(O) or C(═NOH); and all other groups are as defined in Formula Ia.

Another embodiment of embodiment A5 is that where R¹, R², R⁵ and R⁶ arehydrogen.

In another embodiment (A6), the Compound id of Formula Ia where the Aring is phenylene optionally substituted with one, two, three, or fourgroups selected from R¹⁰, R¹², R¹⁴, and R¹⁶; X, R⁷, R¹⁰, R¹², R¹⁴, andR¹⁶ are as defined for a Compound of Formula Ia; and

-   R³ and R⁴ are independently halo, nitro, —NR⁸R^(8′), —OR⁸,    —NHS(O)₂R⁸, —CN, —S(O)_(m)R⁸, —S(O)₂N⁸R^(8′), —C(O)R⁸, —C(O)OR⁸,    —C(O)NR⁸R^(8′), —NR⁸C(O)OR^(8′), —NR⁸C(O)NR^(8′)R^(8″),    —NR⁸C(O)OR^(8′), —NR⁸C(O)R^(8′), lower alkanyl, lower alkenyl, lower    alkynyl, cycloalkyl, heteroaryl, or heterocycloalkyl; where the    lower alkanyl, lower alkenyl, lower alkynyl, cycloalkyl, heteroaryl,    and heterocycloalkyl are independently optionally substituted with    one, two, three, four, five, six or seven groups independently    selected from halo, lower alkanyl, haloalkyl, nitro, optionally    substituted cycloalkyl, optionally substituted heterocycloalkyl,    optionally substituted aryl, optionally substituted arylalkyl,    optionally substituted heteroaryl, —OR⁸, —NR⁸R^(8′), —NR⁸S(O)₂R⁹,    —CN, —S(O)_(m)R⁹, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′),    —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′) and —NR⁸C(O)R^(8′); or    R³ and R⁴ together with the carbon to which they are attached form    C(O) or C(═NOH); and all other groups are as defined in Formula Ia.

Another embodiment of embodiment A6 is that where R¹, R², R⁵ and R⁶ arehydrogen.

In another embodiment (A7), the invention provides a Compound of FormulaIa where the A ring is phenylene optionally substituted with R¹⁰, R¹²,R¹⁴, and R¹⁶ where R¹⁴ and R¹⁶ are hydrogen and where R¹⁰ and R¹² areindependently hydrogen or halo; X and R⁷ are halo; R¹, R², R⁵ and R⁶ arehydrogen; and

-   R³ is hydrogen and R⁴ is —NR⁸R^(8′) (where R⁸ is hydrogen, hydroxy,    lower alkanyl, alkoxy, aryl, cycloalkyl, heteroaryl, or    heterocycloalkyl and R^(8′) is hydroxy, alkoxy, aryl, cycloalkyl,    heteroaryl, or heterocycloalkyl), —NHS(O)₂R⁸, —CN, —S(O)_(m)R⁸,    —S(O)₂NR⁸R^(8′), —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′), —NR⁸C(O)OR^(8′),    —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′), —NR⁸C(O)R^(8′), lower    alkenyl, and lower alkynyl; where the lower alkenyl and lower    alkynyl are optionally substituted with one, two, three, four, five,    six or seven groups independently selected from halo, lower alkanyl,    haloalkyl, nitro, optionally substituted cycloalkyl, optionally    substituted heterocycloalkyl, optionally substituted aryl,    optionally substituted arylalkyl, optionally substituted heteroaryl,    —OR⁸, —NR⁸R^(8′), —NHS(O)₂R⁹, —CN, —S(O)_(m)R⁹, —C(O)R⁸, —C(O)OR⁸,    —C(O)NR⁸R^(8′), —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′) and    —NR⁸C(O)R^(8′); or-   R³ and R⁴ together with the carbon to which they are attached form    C(O) or C(═NOH);-   m, R^(8″), and R⁹ are as defined for a Compound of Formula Ia; and    unless otherwise specified in this embodiment, R⁸ and R^(8′), and    all other groups, are as defined in the Summary of the Invention for    a Compound of Formula la.

In another embodiment of the Invention (A8), the invention provides aCompound of Formula I or Ia where the A ring is phenylene optionallysubstituted with one, two, three, or four groups selected from R¹⁰, R¹²,R¹⁴, and R¹⁶; R³ is hydrogen, halo, hydroxy, alkoxy, or amino; and allother groups are as defined in Formula I or Ia, respectively. In anotherembodiment, R³ is hydrogen, fluoro, hydroxy, methoxy, or amino. In yetanother embodiment, R³ is hydrogen or hydroxy. In another embodiment, R³is hydroxy.

In another embodiment of embodiment A8, X and R⁷ are halo; A isphenylene optionally substituted with R¹⁰, R¹², R¹⁴, and R¹⁶ where R¹⁴and R¹⁶ are hydrogen and where R¹⁰ and R¹² are independently hydrogen orhalo; R¹, R², R⁵ and R⁶ are hydrogen; and R⁴ is as defined in Formula Ior Ia, respectively.

In another embodiment of the Invention (A9), the invention provides aCompound of Formula Ia where the A ring is phenylene optionallysubstituted with one, two, three, or four groups selected from R¹⁰, R¹²,R¹⁴, and R¹⁶; R¹, R², R⁵ and R⁶ are hydrogen; R³ is hydrogen, halo,hydroxy, alkoxy, or amino; and R⁴ is heterocycloalkyl, heteroaryl, oralkyl substituted with —NR⁸R^(8′) where R⁸ and R^(8′) and all othergroups are as defined in Formula Ia.

Another embodiment of embodiment A9 is that where R⁴ is alkylsubstituted with —NR⁸R^(8′) where R⁸ and R^(8′) and all other groups areas defined in Formula Ia. In another embodiment, the compound is ofFormula I(c) or I(d):

where R³ is as defined in A9; X, R⁷, R⁸, R^(8′), R¹⁰, R¹², R¹⁴, and R¹⁶are as defined in Formula Ia.

Another embodiment of embodiment A9 is that where R⁴ isheterocycloalkyl.

In another embodiment of embodiment A9, the compound is that where X andR⁷ are halo; A is phenylene optionally substituted with R¹⁰, R¹², R¹⁴,and R¹⁶ where R¹⁴ and R¹⁶ are hydrogen and where R¹⁰ and R¹² areindependently hydrogen or halo; R³ is hydroxy; and R⁴ is alkylsubstituted with —NR⁸R^(8′) or R⁴ is heterocycloalkyl optionallysubstituted with one, two, or three groups independently selected fromhalo, lower alkanyl, haloalkyl, nitro, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, optionally substituted arylalkyl, optionallysubstituted heteroaryl, —OR⁸, —NR⁸R^(8′), —NHS(O)₂R⁹, —CN, —S(O)_(m)R⁹,—C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′), —NR⁸C(O)NR^(8′)R^(8″),—NR⁸C(O)OR^(8′) and —NR⁸C(O)R^(8′); and where m, R³, R⁸, R^(8′), R^(8″),and R⁹ are as defined in Formula Ia.

In another embodiment of the Invention (A10), the invention provides aCompound of Formula Ia where the A ring is phenylene optionallysubstituted with one, two, three, or four groups selected from R¹⁰, R¹²,R¹⁴, and R¹⁶;

-   R⁴ is    -   a) hydrogen;    -   b) lower alkanyl;    -   c) lower alkanyl substituted with one or two —OR⁸ where R⁸ is        hydrogen, aryl, or lower alkanyl where the lower alkanyl in R⁸        is substituted with one or two hydroxy;    -   d) lower alkanyl substituted with one, two, or three halo;    -   e) lower alkanyl substituted with nitro;    -   f) lower alkanyl substituted with —S(O)_(m)R⁹ (where m is 0 and        R⁹ is aryl);    -   g) lower alkanyl substituted with optionally substituted        heterocycloalkyl;    -   h) lower alkenyl;    -   i) —NR⁸R^(8′) (where R⁸ and R^(8′) are independently hydrogen;        lower alkanyl; lower alkenyl; lower alkanyl substituted with one        or two hydroxy; lower alkanyl substituted with one or two        —NR³⁰R^(30′) where R³⁰ and R^(30′) are independently hydrogen,        alkyl, or hydroxyalkyl; lower alkanyl substituted with        optionally substituted heteroaryl; or lower alkanyl substituted        with optionally substituted cycloalkyl);    -   j) —C(O)NR⁸R^(8′) (where R⁸ is hydrogen, lower alkanyl, or lower        alkenyl; and R^(8′) is hydrogen; hydroxy; lower alkanyl; lower        alkenyl; lower alkanyl substituted with one or two hydroxy;        lower alkanyl substituted with optionally substituted        heterocycloalkyl; lower alkanyl substituted with —NR³⁰R^(30′)        where R³⁰ and R^(30′) are independently hydrogen, alkyl, or        hydroxyalkyl; or alkoxy);    -   k) —NR⁸C(O)OR^(8′) (where R⁸ and R^(8′) are independently        hydrogen, lower alkanyl, or lower alkenyl);    -   l) lower alkanyl substituted with —NR⁸R^(8′) (where R⁸ is        hydrogen, lower alkanyl, lower alkenyl, lower alkynyl, or lower        alkanyl substituted with one or two hydroxy; and R^(8′) is        hydrogen; hydroxy; alkoxy; lower alkanyl; lower alkenyl; lower        alkynyl; alkoxy; lower alkanyl substituted with one or two        hydroxy; lower alkanyl substituted with one or two alkoxy; lower        alkanyl substituted with —NR³⁰R^(30′) where R³⁰ and R^(30′) are        independently hydrogen, lower alkanyl, or hydroxyalkyl; lower        alkanyl substituted with one or two hydroxy and one or two        —NR³⁰R^(30′) where R³⁰ and R^(30′) are independently hydrogen,        lower alkanyl, or hydroxyalkyl; lower alkanyl substituted with        one, two, three, four, or five halo; lower alkanyl substituted        with optionally substituted cycloalkyl; lower alkanyl        substituted with optionally substituted aryl; lower alkanyl        substituted with one or two hydroxy and one optionally        substituted aryl; lower alkanyl substituted with optionally        substituted heterocycloalkyl; lower alkanyl substituted with        optionally substituted heteroaryl; heteroaryl; aryl; aryl        substituted with one or two hydroxy; aryl substituted with one        or two alkoxy; aryl substituted with one or two halo; aryl        substituted with one or two —NR³²C(O)R^(32a) where R³² is        hydrogen or lower alkanyl and R^(32a) is lower alkanyl, lower        alkenyl, alkoxy, or cycloalkyl; aryl substituted with        —NR³⁴SO₂R^(34a) where R³⁴ is hydrogen or lower alkanyl and        R^(34a) is lower alkanyl, lower alkenyl, cycloalkyl, aryl,        heteroaryl, or heterocycloalkyl; cycloalkyl; cycloalkyl        substituted with one or two hydroxy; cycloalkyl substituted with        one or two hydroxy and one or two hydroxyalkyl; cycloalkyl        substituted with one or two alkoxy; cycloalkyl substituted with        carboxy; cycloalkyl substituted with —C(O)NR³³R^(33a) where R³³        is hydrogen or lower alkanyl and R^(33a) is lower alkanyl, lower        alkenyl, lower alkynyl, or cycloalkyl; lower alkanyl substituted        with —C(O)NR³³R^(33a) where R³³ is hydrogen or lower alkanyl and        R^(33a) is lower alkanyl, lower alkenyl, lower alkynyl, or        cycloalkyl; cycloalkyl substituted with optionally substituted        cycloalkyl; heterocycloalkyl; heterocycloalkyl substituted with        lower alkanyl ; heterocycloalkyl substituted with        alkoxycarbonyl; heterocycloalkyl substituted with optionally        substituted arylalkyl; heterocycloalkyl substituted with one or        two hydroxy; heterocycloalkyl substituted with one or two        alkoxy; heterocycloalkyl substituted with one or two        hydroxyalkyl; heterocycloalkyl substituted with one or two        hydroxy, one or two alkoxy, and one or two hydroxyalkyl; lower        alkanyl substituted with optionally substituted aryloxy; lower        alkanyl substituted with —S(O)_(n)R³¹ where n is 0 and R³¹ is        lower alkanyl; lower alkanyl substituted with carboxy; lower        alkanyl substituted with alkoxycarbonyl; or lower alkanyl        substituted with —NR³²C(O)R^(32a) where R³² is hydrogen or lower        alkanyl and R^(32a) is lower alkanyl, lower alkenyl, alkoxy, or        cycloalkyl);    -   m) —NR⁸C(O)R^(8′) (where R⁸ is hydrogen, lower alkanyl, or lower        alkenyl; and R^(8′) is hydrogen; lower alkanyl; lower alkanyl        substituted with one or two hydroxy; lower alkanyl substituted        with optionally substituted heterocycloalkyl; lower alkanyl        substituted with —NR³⁰R^(30′) where R³⁰ and R^(30′) are        independently hydrogen, lower alkanyl, hydroxyalkyl, or lower        alkenyl);    -   n) cycloalkyl;    -   o) cycloalkyl substituted with —NR⁸R^(8′) where R⁸ and R^(8′)        are independently hydrogen, lower alkanyl, or lower alkenyl;    -   p) heterocycloalkyl;    -   q) heterocycloalkyl substituted with —NR⁸R^(8′) where R⁸ and        R^(8′) are independently hydrogen, lower alkanyl, or lower        alkenyl;    -   r) heterocycloalkyl substituted with one or two lower alkanyl;    -   s) heterocylcloalkyl substituted with —C(O)OR⁸ where R⁸ is lower        alkanyl or lower alkenyl;    -   t) lower alkanyl substituted with —NR⁸C(O)R^(8′) (where R⁸ is        hydrogen, lower alkanyl, or lower alkenyl and R^(8′) is lower        alkanyl; lower alkenyl; or lower alkanyl substituted with        alkoxy, aryl, and one, two, or three halo);    -   u) heteroaryl;    -   v) heteroaryl substituted with —NR⁸R^(8′) where R⁸ and R^(8′)        are independently hydrogen, lower alkanyl, or lower alkenyl;        lower alkanylsubstituted with optionally substituted heteroaryl;    -   w) lower alkanyl substituted with —NR⁸S(O)₂R⁹ where R⁸ is        hydrogen, lower alkanyl, or lower alkenyl and R⁹ is lower        alkanyl or lower alkenyl;    -   x) lower alkanyl substituted with —NR⁸C(O)OR^(8′) where R⁸ and        R^(8′) are independently hydrogen, lower alkanyl, or lower        alkenyl;    -   y) lower alkanyl substituted with one aryl and one —NR⁸R^(8′)        where R⁸ and R^(8′) are independently hydrogen, lower alkanyl,        or lower alkenyl; or    -   z) lower alkanyl substituted with one or two —OR⁸ (where R⁸ is        hydrogen) and one or two —NR⁸R^(8′) where R⁸ and R^(8′) are        independently hydrogen, lower alkanyl, or lower alkenyl; and        all other groups are as defined for a Compound of Formula Ia.

Another embodiment of embodiment A10 is that wherein X and R⁷ are halo;A is phenylene optionally substituted with R¹⁰, R¹², R¹⁴, and R¹⁶ whereR¹⁴ and R¹⁶ are hydrogen and where R¹⁰ and R¹² are independentlyhydrogen or halo; R¹, R², R⁵ and R⁶ are hydrogen; and R³ is hydrogen,halo, hydroxy, alkoxy, or amino.

Another embodiment of embodiment A10 is that where R³ is hydrogen and R⁴is

-   -   a) hydrogen;    -   b) —NR⁸R^(8′) (where R⁸ and R^(8′) are independently hydrogen;        lower alkanyl; lower alkenyl; lower alkanyl substituted with one        or two hydroxy; lower alkanyl substituted with one or two        —NR³⁰R^(30′) where R³⁰ and R^(30′) are independently hydrogen,        lower alkanyl, or hydroxyalkyl; lower alkanyl substituted with        optionally substituted heteroaryl; or lower alkanyl substituted        with optionally substituted cycloalkyl);    -   c) —C(O)NR⁸R^(8′) (where R⁸ is hydrogen, lower alkanyl, or lower        alkenyl; and R^(8′) is hydrogen; bydroxy; lower alkanyl; lower        alkenyl; lower alkanyl substituted with one or two hydroxy;        lower alkanyl substituted with heterocycloalkyl; lower alkanyl        substituted with —NR³⁰R^(30′) where R³⁰ and R^(30′) are        independently hydrogen, lower alkanyl, or hydroxyalkyl; alkoxy;        or substituted alkoxy);    -   d) —NR⁸C(O)OR^(8′) (where R⁸ and R^(8′) are independently        hydrogen, lower alkanyl, or lower alkenyl);    -   e) —NR⁸C(O)R^(8′) (where R⁸ is hydrogen, lower alkanyl, or lower        alkenyl; and R^(8′) is hydrogen; lower alkanyl; lower alkanyl        substituted with one or two hydroxy; lower alkanyl substituted        with optionally substituted heterocycloalkyl; lower alkanyl        substituted with —NR³⁰R^(30′) where R³⁰ and R^(30′) are        independently hydrogen, lower alkanyl, hydroxyalkyl, or lower        alkenyl);    -   f) lower alkanyl;    -   g) lower alkanyl substituted with one or two —OR⁸ (where R⁸ is        hydrogen);    -   h) lower alkanyl substituted with —NR⁸R^(8′) (where R⁸ is        hydrogen, lower alkanyl, lower alkenyl, lower alkynyl, or lower        alkanyl substituted with one or two hydroxy; and R^(8′) is        hydrogen; lower alkanyl; lower alkenyl; lower alkynyl; lower        alkanyl substituted with one or two hydroxy; heterocycloalkyl        substituted with lower alkanyl; or lower alkanyl substituted        with —NR³⁰R^(30′) where R³⁰ and R^(30′) are independently        hydrogen, lower alkanyl, or hydroxyalkyl);    -   i) heterocycloalkyl; or    -   j) heterocycloalkyl substituted with —NR⁸R^(8′) (where R⁸ and        R^(8′) are independently hydrogen, lower alkanyl, or lower        alkenyl).

Another embodiment of embodiment A10 is that where R³ is alkoxy and R⁴is lower alkanyl substituted with —NR⁸R^(8′) (where R⁸ and R^(8′) areindependently hydrogen, lower alkanyl, or lower alkenyl). In anotherembodiment, R³ is methoxy and R⁴ is lower alkanyl substituted with—NR⁸R^(8′) (where R⁸ and R^(8′) are independently hydrogen, loweralkanyl, or lower alkenyl).

Another embodiment of embodiment A10 is that where R³ is halo and R⁴ islower alkanyl substituted with —NR⁸R^(8′) (where R⁸ and R^(8′) areindependently hydrogen, lower alkanyl, or lower alkenyl). In anotherembodiment, R³ is fluoro and R⁴ is lower alkanyl substituted with—NR⁸R^(8′) (where R⁸ and R^(8′) are independently hydrogen, loweralkanyl, or lower alkenyl).

Another embodiment of embodiment A10 is that where R³ is amino and R⁴ islower alkanyl substituted with —NR⁸R^(8′) (where R⁸ and R^(8′) areindependently hydrogen, lower alkanyl, or lower alkenyl).

Another embodiment of embodiment A10 is that where R³ is hydroxy and R⁴is

-   -   a) hydrogen;    -   b) lower alkanyl;    -   c) lower alkenyl;    -   d) lower alkanyl substituted with one or two —OR⁸ where R⁸ is        hydrogen, aryl, or lower alkanyl where the lower alkanyl in R⁸        is substituted with one or two hydroxy;    -   e) lower alkanyl substituted with one, two, or three halo;    -   f) lower alkanyl substituted with nitro;    -   g) lower alkanyl substituted with —S(O)_(m)R⁹ (where m is 0 and        R⁹ is aryl);    -   h) lower alkanyl substituted with optionally substituted        heterocycloalkyl;    -   i) lower alkanyl substituted with —NR⁸R^(8′) (where R⁸ is        hydrogen, lower alkanyl, lower alkenyl, lower alkynyl, or lower        alkanyl substituted with one or two hydroxy; and R^(8′) is        hydrogen; hydroxy; alkoxy; lower alkanyl; lower alkenyl; lower        alkynyl; alkoxy; substituted alkoxy; lower alkanyl substituted        with one or two hydroxy; lower alkanyl substituted with        —NR³⁰R^(30′) where R³⁰ and R^(30′) are independently hydrogen,        lower alkanyl, or hydroxyalkyl; lower alkanyl substituted with        one or two hydroxy and one or two —NR³⁰R^(30′) where R³⁰ and        R^(30′) are independently hydrogen, lower alkanyl, or        hydroxyalkyl; heterocycloalkyl substituted with lower alkanyl,        alkoxycarbonyl, or optionally substituted arylalkyl; lower        alkanyl substituted with one, two, three, four, or five halo;        lower alkanyl substituted with optionally substituted        cycloalkyl; lower alkanyl substituted with optionally        substituted aryl; lower alkanyl substituted with one or two        hydroxy and one optionally substituted aryl; lower alkanyl        substituted with optionally substituted heterocycloalkyl; lower        alkanyl substituted with optionally substituted heteroaryl;        heteroaryl; aryl; aryl substituted with one or two hydroxy; aryl        substituted with one or two alkoxy; aryl substituted with one or        two halo; aryl substituted with one or two —NR³²C(O)R^(32a)        where R³² is hydrogen or lower alkanyl and R^(32a) is lower        alkanyl, lower alkenyl, alkoxy, or cycloalkyl; aryl substituted        with —NR³⁴SO₂R^(34a) where R³⁴ is hydrogen or lower alkanyl and        R^(34a) is lower alkanyl, lower alkenyl, cycloalkyl, aryl,        heteroaryl, or heterocycloalkyl; cycloalkyl; cycloalkyl        substituted with one or two hydroxy; cycloalkyl substituted with        one or two hydroxy and one or two hydroxyalkyl; cycloalkyl        substituted with one or two alkoxy; cycloalkyl substituted with        carboxy; cycloalkyl substituted with —C(O)NR³³R^(33a) where R³³        is hydrogen or alkyl and R^(33a) is lower alkanyl, lower        alkenyl, lower alkynyl, or cycloalkyl; cycloalkyl substituted        with optionally substituted cycloalkyl; heterocycloalkyl;        heterocycloalkyl substituted with one or two hydroxy;        heterocycloalkyl substituted with one or two alkoxy;        heterocycloalkyl substituted with one or two hydroxyalkyl;        heterocycloalkyl substituted with one or two hydroxy, one or two        alkoxy, and one or two hydroxyalkyl; lower alkanyl substituted        with —C(O)NR³³R^(33a) where R³³ is hydrogen or alkyl and R^(33a)        is lower alkanyl, lower alkenyl, lower alkynyl, or cycloalkyl;        lower alkanyl substituted with optionally substituted aryloxy;        lower alkanyl substituted with —S(O)_(n)R³¹ where n is 0 and R³¹        is lower alkanyl; lower alkanyl substituted with carboxy; lower        alkanyl substituted with alkoxycarbonyl; or lower alkanyl        substituted with —NR³²C(O)R^(32a) where R³² is hydrogen or lower        alkanyl and R^(32a) is lower alkanyl, lower alkenyl, alkoxy, or        cycloalkyl);    -   j) heterocycloalkyl;    -   k) —C(O)NR⁸R^(8′) (where R⁸ is hydrogen, lower alkanyl, or lower        alkenyl; and R^(8′) is hydrogen; lower alkanyl; lower alkenyl;        or substituted with one or two hydroxy;);    -   l) lower alkanyl substituted with —NR⁸C(O)R^(8′) (where R⁸ is        hydrogen, lower alkanyl, or lower alkenyl and R^(8′) is lower        alkanyl; lower alkenyl; or lower alkanyl substituted with        alkoxy, aryl, and one, two, or three halo);    -   m) cycloalkyl;    -   n) cycloalkyl substituted with —NR⁸R^(8′) where R⁸ and R^(8′)        are independently hydrogen, lower alkanyl, or lower alkenyl;    -   o) cycloalkyl substituted with —C(O)NR³³R^(33a) where R³³ is        hydrogen or lower alkanyl and R^(33a) is lower alkanyl, lower        alkenyl, lower alkynyl, or cycloalkyl;    -   p) heterocycloalkyl;    -   q) heterocycloalkyl substituted with one or two lower alkanyl;    -   r) heterocylcloalkyl substituted with —C(O)OR⁸ where R⁸ is lower        alkanyl or lower alkenyl;    -   s) heteroaryl;    -   t) heteroaryl optionally substituted with —NR⁸R^(8′) where R⁸        and R^(8′) are independently hydrogen, lower alkanyl, or lower        alkenyl;    -   u) lower alkanyl substituted with optionally substituted        heteroaryl;    -   v) lower alkanyl substituted with —NR⁸S(O)₂R⁹ where R⁸ is        hydrogen, lower alkanyl, or lower alkenyl and R⁹ is lower        alkanyl or lower alkenyl;    -   w) lower alkanyl substituted with —NR⁸C(O)OR^(8′) where R⁸ and        R^(8′) are independently hydrogen, lower alkanyl, or lower        alkenyl;    -   x) lower alkanyl substituted with one aryl and one —NR⁸R^(8′)        where R⁸ and R^(8′) are independently hydrogen, lower alkanyl,        or lower alkenyl; or    -   y) lower alkanyl substituted with one or two —OR⁸ (where R⁸ is        hydrogen) and one or two —NR⁸R^(8′) where R⁸ and R^(8′) are        independently hydrogen, lower alkanyl, or lower alkenyl.

Another embodiment of the Invention (A11) provides a compound of FormulaI or Ia where the A ring is phenylene optionally substituted with R¹⁰,R¹², R¹⁴, and R¹⁶; R³ and R⁴ together with the carbon to which they areattached form C(O) or C(═NOH); and all other groups are as defined for aCompound of Formula I or Ia, respectively. In another embodiment, X andR⁷ are halo; A is phenylene optionally substituted with with R¹⁰, R¹²,R¹⁴, and R¹⁶ where R¹⁴ and R¹⁶ are hydrogen and where R¹⁰ and R¹² areindependently hydrogen or halo; R¹, R², R⁵ and R⁶ are hydrogen; and R³and R⁴ together with the carbon to which they are attached form C(O) orC(═NOH).

Another embodiment of the Invention (A12) provides a Compound of FormulaI or Ia where the A ring is phenylene optionally substituted with R¹⁰,R¹², R¹⁴, and R¹⁶ where R¹⁴ and R¹⁶ are hydrogen and where R¹⁰ and R¹²are independently hydrogen or halo; X and R⁷ are halo; and R¹, R², R⁴,R⁵ and R⁶ are hydrogen; and all other groups are as defined in Formula Ior Ia, respectively.

Another embodiment of the Invention (A14) provides a Compound of FormulaI or Ia where the A ring is phenylene optionally substituted with R¹⁰,R¹², R¹⁴, and R¹⁶; R¹ is hydrogen; and R² is alkyl substituted with—NR⁸R^(8′); where R⁸ and R^(8′) and all other groups are as defined inFormula I or Ia, respectively.

Another embodiment of the Invention (A15) provides a Compound Formula Ior Ia where the A ring is phenylene optionally substituted with R¹⁰,R¹², R¹⁴, and R¹⁶; R⁷ is iodo or bromo; X is fluoro or chloro; R¹, R²,R⁵, and R⁶ are hydrogen; and R¹⁰, R¹², R¹⁴, and R¹⁶ are independentlyhydrogen or fluoro; and all other groups are as defined in Formula I orIa, respectively. In another embodiment, R¹⁰ is 3-fluoro and R¹², R¹⁴,and R¹⁶ are hydrogen or halo; R¹⁰ is 3-fluoro, R¹² is 4-fluoro, and R¹⁴and R¹⁶ are hydrogen; R¹⁰ is 4-fluoro, R¹² is 5-fluoro, and R¹⁴ and R¹⁶are hydrogen; R¹⁰ is 4-fluoro, R¹² is 6-fluoro, and R¹⁴ and R¹⁶ arehydrogen; or R¹² is 4-fluoro and R¹⁰, R¹⁴, and R¹⁶ are hydrogen.

In another embodiment, the invention is a compound of Formula I or Iawhere the A ring is phenylene optionally substituted with R¹⁰, R¹², R¹⁴,and R¹⁶; R³ is hydroxy and R⁴ is heterocycloalkyl, lower alkanyl, orheteroaryl, where the lower alkanyl is optionally substituted with—NR⁸R^(8′) (where R⁸ is hydrogen or lower alkanyl and R^(8′) ishydrogen, lower alkanyl, or cycloalkyl where the cycloalkyl isoptionally substituted with groups independently selected from hydroxyand lower alkanyl) and the heteroaryl is optionally substituted withlower alkanyl; and all other groups are as defined in Formula I or Ia,respectively. In another embodiment, R³ is hydroxy and R⁴ isheterocycloalkyl or lower alkanyl, where the lower alkanyl is optionallysubstituted with —NR⁸R^(8′) (where R⁸ is hydrogen or lower alkanyl andR^(8′) is hydrogen, lower alkanyl, or cycloalkyl where the cycloalkyl isoptionally substituted with groups independently selected from hydroxyand lower alkanyl).

Another embodiment of the invention is a compound of Formula II:

and optionally as a pharmaceutically acceptable salt or solvate thereof,wherein X, R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ are as defined above forFormula I, and R¹⁰, R¹², R¹⁴ and R¹⁶ are independently selected fromhydrogen, lower alkanyl, lower alkenyl, lower alkynyl, halo, haloalkoxy,hydroxy, lower alkoxy, amino, alkylamino, dialkylamino, haloalkyl,—NHS(O)₂R⁸, —CN, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′) and —NR⁸C(O)R^(8′).

In another embodiment of Formula II, R⁷ and X are halo and R¹⁰, R¹², R¹⁴and R¹⁶ are independently selected from hydrogen and halo.

Another embodiment of the invention is a Compound of Formula III:

and optionally as a pharmaceutically acceptable salt or solvate thereof,wherein X, R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ are as defined above for aCompound of Formula I.

In another embodiment of Formula III, X and R⁷ are halo. In anotherembodiment, X is fluoro or chloro and R⁷ is iodo or bromo.

In another embodiment of Formula III, R³ is halo, nitro, —NR⁸R^(8′),—OR⁸, —NHS(O)₂R⁸, —CN, —S(O)_(m)R⁸, —S(O)₂NR⁸R^(8′), —C(O)R⁸, —C(O)OR⁸,—C(O)NR⁸R^(8′), —NR⁸C(O)OR^(8′), —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′),—NR⁸C(O)R^(8′), lower alkanyl, lower alkenyl, lower alkynyl, cycloalkyl,heteroaryl, or heterocycloalkyl; where the lower alkanyl, lower alkenyl,lower alkynyl, cycloalkyl, heteroaryl, and heterocycloalkyl areindependently optionally substituted with one, two, three, four, five,six or seven groups independently selected from halo, lower alkanyl,haloalkyl, nitro, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, optionallysubstituted arylalkyl, optionally substituted heteroaryl, —OR⁸,—NR⁸R^(8′), —NR⁸S(O)₂R⁹, —CN, —S(O)_(m)R⁹, —C(O)R⁸, —C(O)OR⁸,—C(O)NR⁸R^(8′), —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′) and—NR⁸C(O)R^(8′) and R⁴ is as defined in Formula III; or R³ and R⁴together with the carbon to which they are attached form C(O) orC(═NOH); and all other groups are as defined in Formula III. Morespecifically, R¹, R², R⁵ and R⁶ are hydrogen; and X and R⁷ are halo.

In another embodiment of Formula III, R³ and R⁴ are independently halo,nitro, —NR⁸R^(8′), —OR⁸, —NHS(O)₂R⁸, —CN, —S(O)_(m)R⁸, —S(O)₂NR⁸R^(8′),—C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′), —NR⁸C(O)OR^(8′),—NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′), —NR⁸C(O)R^(8′), lower alkanyl,lower alkenyl, lower alkynyl, cycloalkyl, heteroaryl, orheterocycloalkyl; where the lower alkanyl, lower alkenyl, lower alkynyl,cycloalkyl, heteroaryl, and heterocycloalkyl are independentlyoptionally substituted with one, two, three, four, five, six or sevengroups independently selected from halo, lower alkanyl, haloalkyl,nitro, optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, optionally substitutedarylalkyl, optionally substituted heteroaryl, —OR⁸, —NR⁸R^(8′),—NR⁸S(O)₂R⁹, —CN, —S(O)_(m)R⁹, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′),—NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′) and —NR⁸C(O)R^(8′); or R³ and R⁴together with the carbon to which they are attached form C(O) orC(═NOH); and all other groups are as defined in Formula III. In anotherembodiment, R¹, R², R⁵ and R⁶ are hydrogen; and X and R⁷ are halo.

In another embodiment of the invention (B5), the invention provides aCompound of Formula I where the A ring is thien-diyl and X, R¹, R², R³,R⁴, R⁵, R⁶, R⁷, R¹⁰, and R¹² are as defined in Formula I. In anotherembodiment, the A ring is thien-3,4-diyl; R¹⁰ and R¹² are hydrogen; Xand R⁷ are halo; and R¹, R², R⁵, and R⁶ are hydrogen. In anotherembodiment, X is fluoro or chloro; R⁷ is iodo or bromo; R³ is hydrogenor hydroxy; and R⁴ is —NR⁸R^(8′) (where R⁸ and R^(8′) are independentlyhydrogen or lower alkanyl), heterocycloalkyl, heteroaryl (optionallysubstituted with lower alkanyl), or lower alkanyl where the loweralkanyl is optionally substituted with —NR⁸R^(8′) (where R⁸ is hydrogenor lower alkanyl and R^(8′) is hydrogen, lower alkanyl, or cycloalkylwhere the cycloalkyl is optionally substituted with one or two groupsindependently selected from hydroxy and lower alkanyl).

Another embodiment of the invention is a compound of Formula IV:

and optionally as a pharmaceutically acceptable salt or solvate thereof,wherein the A ring, R¹, R², R³, R⁴, R⁵, and R⁶ are as defined above forFormula I.

Another embodiment of the invention is a compound of Formula V:

and optionally as a pharmaceutically acceptable salt or solvate thereof,wherein the A ring, R³, R⁴, and R⁷ are as defined above for Formula I.

Another embodiment of the Invention (E) is directed to a Compound ofFormula Ia where

-   the A ring is phenylene optionally substituted with one or two    groups selected from R¹⁰, R¹², R¹⁴, and R¹⁶ where R¹⁰, R¹², R¹⁴ and    R¹⁶ are independently hydrogen or halo;-   X is halo;-   R¹, R², R⁵ and R⁶ are hydrogen;-   R³ is hydrogen, halo, hydroxy, alkoxy, or amino;-   R⁴ is hydrogen, halo, —NR⁸R^(8′), —C(O)OR⁸, —C(O)NR⁸R^(8′),    —NR⁸C(O)OR^(8′), —NR⁸C(O)R^(8′), lower alkanyl, lower alkenyl,    cycloalkyl, heterocycloalkyl, or heteroaryl; where the R⁴ lower    alkanyl is optionally substituted with one, two, or three groups    independently selected from —OR⁸, halo, nitro, —S(O)_(m)R⁹,    optionally substituted heterocycloalkyl, —NR⁸R^(8′), —NR⁸C(O)R^(8′),    —NR⁸S(O)₂R⁹, —NR⁸C(O)OR^(8′), and aryl; where the R⁴ cycloalkyl is    optionally substituted with one or two groups selected from —OR⁸ and    —NR⁸R^(8′); where the R⁴ heterocycloalkyl is optionally substituted    with one or two groups independently selected from lower alkanyl and    —C(O)OR⁸; and where the R⁴ heteroaryl is optionally substituted with    —NR⁸R^(8′); or-   R³ and R⁴ together with the carbon to which they are attached form    C(O) or C(═NOH);-   m is 1 or 2;-   R⁷ is halo;

R⁸ and R^(8′) are independently selected from hydrogen, hydroxy, loweralkanyl, lower alkenyl, lower alkynyl, aryl, heterocycloalkyl,heteroaryl, and cycloalkyl;

-   where the R⁸ and R^(8′) alkyl are independently optionally    substituted with one, two, or three groups independently selected    from hydroxy, —NR³⁰R^(30′) (where R³⁰ and R^(30′) are independently    hydrogen, lower alkanyl, or hydroxyalkyl), optionally substituted    heteroaryl, optionally substituted cycloalkyl), alkoxy, substituted    alkoxy, optionally substituted cycloalkyl, optionally substituted    aryl, optionally substituted heterocycloalkyl, optionally    substituted heteroaryl, —C(O)NR³³R^(33a) (where R³³ is hydrogen or    alkyl and R^(33a) is lower alkanyl, lower alkenyl, lower alkynyl, or    cycloalkyl), optionally substituted aryloxy, —S(O)_(n)R³¹ (where n    is 0 and R³¹ is alkyl), carboxy, alkoxycarbonyl, and    —NR³²C(O)R^(32a) (where R³² is hydrogen or alkyl and R^(32a) is    lower alkanyl, lower alkenyl, alkoxy, or cycloalkyl); or where the    lower alkanyl is optionally substituted with one, two, three, four,    or five halo;-   where the R⁸ and R^(8′) heteroaryl are independently optionally    substituted with one or two groups independently selected from amino    and lower alkanyl;-   where the R⁸ and R^(8′) heterocycloalkyl are independently    optionally substituted with one, two, or three groups independently    selected from lower alkanyl, alkoxycarbonyl, optionally substituted    arylalkyl, hydroxy, alkoxy, and hydroxyalkyl;-   where the R⁸ and R^(8′) aryl are independently optionally    substituted with one or two groups independently selected from    hydroxy, alkoxy, halo, —NR³²C(O)R^(32a) (where R³² is hydrogen or    lower alkanyl and R^(32a) is lower alkanyl, lower alkenyl, alkoxy,    or cycloalkyl), and —NR³⁴SO₂R^(34a) (where R³⁴ is hydrogen or alkyl    and R^(34a) is lower alkanyl, lower alkenyl, cycloalkyl, aryl,    beteroaryl, or heterocycloalkyl); and-   where the R⁸ and R^(8′) cycloalkyl are independently optionally    substituted with one, two, or three groups independently selected    from hydroxy, hydroxyalkyl, alkoxy, carboxy, —C(O)NR³³R^(33a) (where    R³³ is hydrogen or alkyl and R^(33a) is lower alkanyl, lower    alkenyl, lower alkynyl, or cycloalkyl), and optionally substituted    cycloalkyl; and-   R⁹ is lower alkanyl or aryl.

Another embodiment of Embodiment (E) is directed to a Compound ofFormula Ia where

-   R³ is hydrogen, halo, hydroxy, or alkoxy;-   R⁴ is hydrogen, halo, —NR⁸R^(8′), —NHS(O)₂R⁸, —C(O)OR⁸,    —C(O)NR⁸R^(8′), —NR⁸C(O)OR^(8′), —NR⁸C(O)R^(8′), lower alkanyl,    lower alkenyl, or heterocycloalkyl; where the R⁴ lower alkanyl is    optionally substituted with one, two, or three groups independently    selected from —OR⁸, halo, optionally substituted heterocycloalkyl,    and —NR⁸R^(8′); and where the R⁴ heterocycloalkyl is optionally    substituted with one or two groups independently selected from lower    alkanyl and —C(O)OR⁸; or-   R³ and R⁴ together with the carbon to which they are attached form    C(O) or C(═NOH);-   m is 1 or 2;-   R⁷ is halo;-   R⁸ and R^(8′) are independently selected from hydrogen, hydroxy,    lower alkanyl, and lower alkenyl; where the R⁸ and R^(8′) lower    alkanyl are independently optionally substituted with one, two, or    three groups independently selected from halo, hydroxy, and    —NR³⁰R^(30′) (where R³⁰ and R^(30′) are independently hydrogen,    lower alkanyl, or hydroxyalkyl); and    all other groups are as defined in Embodiment E.

Another embodiment (F) of the Invention is a Compound of Formula Iawhere

-   the A ring is phenylene optionally substituted with one or two    groups selected from R¹⁰, R¹², R¹⁴, and R¹⁶ where R¹⁰, R¹², R¹⁴ and    R¹⁶ are independently hydrogen or halo;-   X is halo;-   R¹, R², R⁵ and R⁶ are hydrogen;-   R³ is hydrogen, halo, hydroxy, or alkoxy;-   R⁴ is —NR⁸R^(8′), —NHS(O)₂R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′),    —NR⁸C(O)OR^(8′), —NR⁸C(O)R^(8′), lower alkanyl, lower alkenyl, or    heterocycloalkyl; where the R⁴ lower alkanyl is optionally    substituted with one, two, or three groups independently selected    from —OR⁸, halo, optionally substituted heterocycloalkyl, and    —NR⁸R^(8′); and where the R⁴ heterocycloalkyl is optionally    substituted with one or two groups independently selected from lower    alkanyl and —C(O)OR⁸; or-   R³ and R⁴ together with the carbon to which they are attached form    C(O) or C(═NOH); and-   R⁸ and R^(8′) are independently selected from hydrogen, hydroxy,    lower alkanyl, and lower alkenyl; where the R⁸ and R^(8′) lower    alkanyl are independently optionally substituted with one, two, or    three groups independently selected from halo, hydroxy, and    —NR³⁰R^(30′) (where R³⁰ and R^(30′) are independently hydrogen,    lower alkanyl, or hydroxyalkyl).

Another embodiment (G) of the Invention is directed to a Compound ofFormula Ia where

-   the A ring is thien-3,4-diyl optionally substituted with one, two,    or three groups independently selected from R¹⁰, R¹², R¹⁴, and R¹⁶    where R¹⁰, R¹², R¹⁴ and R¹⁶ are independently hydrogen, lower    alkanyl, halo, or amino;-   X is halo;-   R¹, R², R⁵ and R⁶ are hydrogen;-   R³ is hydrogen or hydroxy;-   R⁴ is —OR⁸, —NR⁸R^(8′), heterocycloalkyl, heteroaryl, or lower    alkanyl; where the lower alkanyl is optionally substituted with    —NR⁸R^(8′) and where the heteroaryl is optionally substituted with    lower alkanyl;-   R⁷ is halo;-   R⁸ is hydrogen or lower alkanyl; and-   R^(8′) is hydrogen, lower alkanyl, or cycloalkyl; where the    cycloalkyl is optionally substituted with one or two groups    independently selected from hydroxy and lower alkanyl.

Another embodiment of the Invention (H) is directed to a Compound ofFormula Ia where

-   the A ring is thien-3,4-diyl;-   X is halo;-   R¹, R², R⁵ and R⁶ are hydrogen;-   R³ is hydrogen or hydroxy;-   R⁴ is —OR⁸, —NR⁸R^(8′), heterocycloalkyl, or lower alkanyl; where    the lower alkanyl is optionally substituted with —NR⁸R^(8′);-   R⁷ is halo;-   R⁸ is hydrogen or lower alkanyl;-   R^(8′) is hydrogen or lower alkanyl; and    all other groups are as defined in Embodiment E.

Another embodiment of the invention is a pharmaceutical compositioncomprising a compound according to any of Formulas I, Ia, Ic, Id, II,III, IV, and V or a compound as depicted in Table 1, and apharmaceutically acceptable carrier. In another embodiment, the Compoundis according to Formula Ia, according to Formula V, or according toEmbodiment G.

Section I Definitions

As used in this section, the following words and phrases are generallyintended to have the meanings as set forth below, except to the extentthat the context in which they are used indicates otherwise or they areexpressly defined to mean something different.

The symbol “—” means a single bond, “═” means a double bond, “≡” means atriple bond, and

means a single bond and optionally a double bond. When chemicalstructures are depicted or described, unless explicitly statedotherwise, all carbons are assumed to have hydrogen substitution toconform to a valence of four. Sometimes a particular atom in a structureis described in textual Formula as having a hydrogen or hydrogens assubstitution (expressly defined hydrogen), for example, —CH₂CH₂—. It isunderstood by one of ordinary skill in the art that the aforementioneddescriptive techniques are common in the chemical arts to providebrevity and simplicity to description of otherwise complex structures.

“Alkyl” or “lower alkyl” means a (C₁-C₂₀) linear, branched, or cyclichydrocarbon group and combinations thereof, inclusively. For example,“C₈ alkyl” refers to an n-octyl, iso-octyl, cyclohexylethyl, isobutenyl,and but-2-ynyl groups and the like. Examples of lower alkyl groupsinclude methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl,isobutyl, pentyl, hexyl and the like. Exemplary alkyl groups are thoseof C₂₀ or below.

In this application, alkyl includes alkanyl, alkenyl, alkynyl, andcycloalkyl residues (and combinations thereof); it is intended toinclude cyclohexylmethyl, vinyl, allyl, isoprenyl, and the like. Thuswhen an alkyl residue having a specific number of carbons is named, allgeometric isomers having that number of carbons are intended to beencompassed; thus, for example, either “butyl” or “C₄ alkyl” is meant toinclude n-butyl, sec-butyl, isobutyl, t-butyl, isobutenyl and but-2-ynylgroups; and for example, “propyl” or “C₃ alkyl” each include n-propyl,propenyl, and isopropyl.

“Alkanyl” means a linear saturated monovalent hydrocarbon radical of oneto twenty carbon atoms or a branched saturated monovalent hydrocarbonradical of three to 20 carbon atoms, e.g., methyl, ethyl, propyl,2-propyl, butyl (including all isomeric forms), or pentyl (including allisomeric forms), and the like. “Lower alkanyl” means alkanyl having oneto six carbons atoms.

The term “cycloalkyl” means a monocyclic or polycyclic hydrocarbonradical having three to thirteen carbon atoms. The cycloalkyl can besaturated or partially unsaturated, but cannot contain an aromatic ring.Cycloalkyl includes fused, bridged, and spiro ring systems. Examples ofsuch radicals include cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl.

“Optionally substituted cycloalkyl” means a cycloalkyl radical, asdefined herein, that is optionally substituted with one, two, three, orfour groups independently selected from C₁-C₆ alkanyl, C₁-C₆ alkoxy,halo, haloalkyl, haloalkoxy, oxo, hydroxy, cyano, nitro, amino,mono(C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, amino(C₁-C₆)alkyl,mono(C₁-C₆)alkylamino(C₁-C₆)alkyl di(C₁-C₆)alkylamino(C₁-C₆)alkyl,carboxy, carboxy ester, cycloalkyl, hydroxyalkyl, —C(O)NR′R″ (where R′is hydrogen, alkyl, hydroxy, or alkoxy and R″ is hydrogen, alkyl, aryl,or heterocyclyl), optionally substituted heterocycloalkyl, optionallysubstituted heteroaryl, —NR′C(O)R″ (where R′ is hydrogen or alkyl and R″is alkyl, aryl, or heterocyclyl), and —NHS(O)₂R′ (where R′ is alkyl,aryl, or hetercyclyl).

“Alkenyl” means a straight or branched hydrocarbon radical having from 2to 20 carbon atoms and at least one double bond and includes ethenyl,propenyl, 1-but-3-enyl, 1-pent-3-enyl, 1-hex-5-enyl and the like. “Loweralkenyl” is alkenyl having 2-6 carbon atoms.

“Alkynyl” means a straight or branched hydrocarbon radical having from 2to 20 carbon atoms and at least one triple bond and includes ethynyl,propynyl, butynyl, pentyn-2-yl and the like. “Lower alkynyl” is alkynylhaving 2-6 carbon atoms.

“Alkylene” means a straight or branched divalent group consisting solelyof carbon and hydrogen atoms, containing no unsaturation and having fromone to ten carbon atoms, for example, methylene, ethylene, propylene,n-butylene and the like. Alkylene is a subset of alkyl, referring to thesame residues as alkyl, but having two points of attachment and,specifically, fully saturated. Examples of alkylene include ethylene(—CH₂CH₂—), propylene (—CH₂CH2CH₂—), dimethylpropylene(—CH₂C(CH₃)₂CH₂—), and cyclohexylpropylene (—CH₂CH₂CH(C₆H₁₃)).

“Alkylidene” means a straight or branched, divalent group consistingsolely of carbon and hydrogen atoms, having from two to ten carbonatoms, and containing at least one double bond. Representative examplesinclude ethylidene, propylidene, n-butylidene, and the like.

“Alkylidyne” means a straight or branched chain divalent groupconsisting solely of carbon and hydrogen atoms having from two to tencarbon atoms, and containing at least one triple bond, for example,propylid-2-ynyl, n-butylid-1-ynyl, and the like.

“Alkoxy” or “alkoxyl” means —O-alkyl, where the alkyl group includesfrom one to eight carbon atoms of a straight, branched, cyclicconfiguration, unsaturated chains, and combinations thereof attached tothe parent structure through an oxygen atom. Examples include methoxy,ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like.Lower-alkoxy refers to groups containing one to six carbons.

“Substituted alkoxy” means an —OR radical where R is substituted alkylas defined herein. Representative examples include groups such as—OCH₂CH₂OCH₃, and glycol ethers such as polyethyleneglycol and—O(CH₂CH₂O)_(x)CH₃, (where x is an integer of between two and twenty,preferable, between two and ten, and more preferably, between two andfive). Another exemplary substituted alkoxy group is hydroxyalkoxy or—OCH₂(CH₂)_(y)OH (where y is an integer of between one and ten, inanother example y is an integer of between one and four).

“Alkoxyalkyl” means a lower alkyl group, as defined herein, substitutedwith at least one, preferably one, two, or three, alkoxy groups asdefined herein. Representative examples include methoxymethyl and thelike.

“Alkoxycarbonylamino” means a —NR′C(O)OR″ group where R′ is hydrogen,alkyl, hydroxy, or alkoxy and R″ is alkyl.

“Alkylcarbonyloxy” means an —OC(O)R group where R is alkyl, as definedherein.

“Acyl” means a —C(O)R radical where R is alkyl (i.e., one to ten carbonatoms of a straight, branched, or cyclic configuration, and is saturatedor unsaturated) or R is optionally substituted aryl or optionallysubstituted heteroaryl. One or more carbons in the R residue may bereplaced by nitrogen, oxygen or sulfur. Examples include acetyl,benzoyl, propionyl, isobutyryl, t-butoxycarbonyl, benzyloxycarbonyl, andpyridinylcarbonyl, and the like. Lower-acyl refers to groups containingone to six carbons.

“Acylamino” means a —NRR′ group where R is acyl, as defined herein, andR′ is hydrogen or alkyl.

“Alkylamino” means a —NHR radical where R is alkyl as defined herein, oran N-oxide derivative, or a protected derivative thereof, e.g.,methylamino, ethylamino, n-, iso-propylamino, n-, iso-, tert-butylamino,or methylamino-N-oxide, and the like.

“Alkylaminoalkyl” means an alkyl group substituted with one or twoalkylamino groups, as defined herein.

“Alkylaminocarbonyl” means a —C(O)NHR radical where R is Ikyl, asdefined herein.

“Aryl” means a monovalent six- to fourteen-membered, mono- orbi-carbocyclic ring, wherein the monocyclic ring is aromatic and atleast one of the rings in the bicyclic ring is aromatic. Representativeexamples include phenyl, naphthyl, and indanyl, and the like.

“Optionally substituted aryl” means an aryl group, as defined herein,which is optionally substituted with one, two, three, four, of fivegroups selected from halo, haloalkyl, haloalkoxy, hydroxy, loweralkanyl, lower alkenyl, lower alkynyl, alkoxy, carboxy, carboxy ester,amino, alkylamino, dialkylamino, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substitutedheteroaryl, —C(O)NR′R″ (where R′ is hydrogen or alkyl and R″ ishydrogen, alkyl, aryl, or heterocyclyl), —NR′C(O)R″ (where R′ ishydrogen or alkyl and R″ is alkyl, aryl, or heterocyclyl), and—NHS(O)₂R′ (where R′ is alkyl, aryl, or heteroaryl).

“Arylalkyl” means a residue in which an aryl moiety is attached to aparent structure via one of an alkylene, alkylidene, or alkylidynegroup. Examples include benzyl, phenethyl, phenylvinyl, phenylallyl andthe like. “Lower arylalkyl” refers to an arylalkyl where the “alkyl”portion of the group has one to six carbons; this can also be referredto as C₁₋₆ arylalkyl.

“Optionally substituted arylalkyl means an alkyl group substituted withone or two optionally substituted aryl group(s) as defined herein. Inaddition the alkyl group may itself be substituted as described under“substituted alkyl”.

“Arylalkyloxy” means an —OR group where R is arylalkyl, as definedherein.

“Carboxy ester” means a —C(O)OR group where R is lower alkanyl, loweralkenyl, lower alkynyl, cycloalkyl, aryl or arylalkyl, each of which isdefined herein. Representative examples include methoxycarbonyl,ethoxycarbonyl, and benzyloxycarbonyl, and the like.

“Dialkylamino” means a —NRR′ radical where R and R′ are independentlyalkyl as defined herein, or an N-oxide derivative, or a protectedderivative thereof, e.g., dimethylamino, diethylamino,N,N-methylpropylamino or N,N-methylethylamino, and the like.

“Dialkylaminoalkyl” means an alkyl group substituted with one or twodialkylamino groups, as defined herein.

“Dialkylaminocarbonyl” means a —C(O)NRR′ group where R and R′ are alkyl.

“Exo-alkenyl” refers to a double bond that emanates from an annularcarbon, and is not within the ring system.

In some examples, as appreciated by one of ordinary skill in the art,two adjacent groups on an aromatic system may be fused together to forma ring structure. The fused ring structure may contain heteroatoms andmay be optionally substituted with one or more groups. It shouldadditionally be noted that saturated carbons of such fused groups (i.e.saturated ring structures) can contain two substitution groups.

“Fused-polycyclic” or “fused ring system” means a polycyclic ring systemthat contains bridged or fused rings; that is, where two rings have morethan one shared atom in their ring structures. In this application,fused-polycyclics and fused ring systems are not necessarily allaromatic ring systems. Typically, but not necessarily, fused-polycyclicsshare a vicinal set of atoms, for example naphthalene or1,2,3,4-tetrahydro-naphthalene. A spiro ring system is not afused-polycyclic by this definition, but fused polycyclic ring systemsof the invention may themselves have spiro rings attached thereto via asingle ring atom of the fused-polycyclic.

“Haloaloxy” means an —OR′ group where R′ is haloalkyl as defined herein,e.g., trifluoromethoxy or 2,2,2-trifluoroethoxy, and the like.

“Halogen” or “halo” means fluoro, chloro, bromo or iodo.

“Haloalkyl” and “haloaryl” mean an alkyl and an aryl group,respectively, that are substituted with one or more halogens, preferablyone to five halo atoms. Thus, “dihaloaryl,” “dihaloalkyl,” and“trihaloaryl” etc. refer to aryl and alkyl substituted with a pluralityof halogens, but not necessarily a plurality of the same halogen; thus4-chloro-3-fluorophenyl is within the scope of dihaloaryl.

“Heteroatom” refers to O, S, N, or P.

“Heterocyclyl” means a stable three- to fifteen-membered ringsubstituent that consists of carbon atoms and from one to fiveheteroatoms selected from the group consisting of nitrogen, phosphorus,oxygen and sulfur. For purposes of this invention, the heterocyclylsubstituent may be a monocyclic, bicyclic or tricyclic ring system,which may include fused or bridged ring systems as well as spirocyclicsystems. The terms “heterocycloalkyl” and “heteroaryl” are groups thatare encompassed by the broader term “heterocyclyl.” The nitrogen,phosphorus, carbon and sulfur atoms in the heterocyclyl group may beoptionally oxidized to various oxidation states. In a specific example,the group —S(O)₀₋₂—, refers to —S— (sulfide), —S(O)— (sulfoxide), and—SO₂— (sulfone). For convenience, nitrogens, particularly but notexclusively, those defined as annular aromatic nitrogens, are meant toinclude their corresponding N-oxide form, although not explicitlydefined as such in a particular example. Thus, for a compound of theinvention having, for example, a pyridyl ring; the correspondingpyridyl-N-oxide is meant to be included as another compound of theinvention. In addition, annular nitrogen atoms may be optionallyquaternized; and the ring substituent may be partially or fullysaturated or aromatic. Examples of heterocyclyl groups include, but arenot limited to, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl,benzofuranyl, carbazoyl, cinnolinyl, dioxolanyl, indolizinyl,naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl,phenoxazinyl, phthalazinyl, pteridinyl, purinyl, quinazolinyl,quinoxalinyl, quinolinyl, isoquinolinyl, tetrazoyl,tetrahydroisoquinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl,4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl,imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl,oxazolidinyl, triazolyl, isoxazolyl, isoxazolidinyl, morpholinyl,thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl,isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl,octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl,decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl,benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuiryl,tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl,thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, dioxaphospholanyl,and oxadiazolyl.

“Optionally substituted heterocyclyl” means a heterocyclyl group, asdefined herein, optionally substituted with one, two, three, four, orfive groups selected from halo, haloalkyl, haloalkoxy, hydroxy, oxo(valency rules permitting), lower alkanyl, lower alkenyl, lower alkynyl,alkoxy, optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, optionally substitutedheteroaryl, alkylaminoalkyl, dialkylaminoalkyl, carboxy, carboxy ester,—C(O)NR′R″ (where R′ is hydrogen or alkyl and R″ is hydrogen, alkyl,aryl, or heterocyclyl), —NR′C(O)R″ (where R′ is hydrogen or alkyl and R″is alkyl, aryl, or heterocyclyl), amino, alkylamino, dialkylamino, and—NHS(O)₂R′ (where R′ is alkyl, aryl, or heteroaryl).

“Heteroalicyclic” and “heterocycloalkyl” mean a non-aromaticheterocyclyl group, as defined herein. A “heteroalicyclic” or“heterocycloalkyl” may be fully saturated or may contain unsaturation,but is not aromatic. “Heteroalicyclic” or “heterocycloalkyl” may bemonocyclic or bicyclic (including fused, bridged, and spiro ringsystems).

“Optionally substituted heteroalicyclic” and “optionally substitutedheterocycloalkyl” mean, respectively, a heteroalicyclic andheterocycloalkyl ring, each as defined herein, optionally substitutedwith one, two, three, four, or five groups selected from halo,haloalkyl, haloalkoxy, hydroxy, oxo, lower alkanyl, lower alkenyl, loweralkynyl, alkoxy, optionally substituted cycloalkyl, heterocycloalkyl,optionally substituted aryl, optionally substituted heteroaryl,alkylaminoalkyl, dialkylaminoalkyl, carboxy, carboxy ester, —C(O)NR′R″(where R′ is hydrogen or alkyl and R″ is hydrogen, alkyl, aryl, orheterocyclyl), —NR′C(O)R″ (where R′ is hydrogen or alkyl and R″ isalkyl, aryl, or heterocyclyl), amino, alkylamino, dialkylamino, and—NHS(O)₂R′ (where R′ is alkyl, aryl, or heteroaryl).

“Heteroaryl” means a 5- to 12-membered, monocyclic aromatic heterocyclyl(where heterocyclyl is defined herein) or bicyclic heterocyclyl ringsystem (where at least one of the rings in the bicyclic system isaromatic) where the monocyclic ring and at least one of the rings in thebicyclic ring system contains one, two, three, four, or fiveheteroatom(s) selected from nitrogen, oxygen, phosphorous, and sulfur.Representative examples include pyridinyl, imidazolyl, pyrimidinyl,pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, firyl, thienyl, isoxazolyl,thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl,indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl,indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl,pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl,furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl,benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, andfuropyridinyl. Fused, bridged, and spiro moieties are also includedwithin the scope of this definition.

“Optionally substituted heteroaryl” means a heteroaryl group, as definedherein, optionally substituted with one, two, three, four, or fivegroups selected from halo, haloalkyl, haloalkoxy, lower alkanyl, loweralkenyl, lower alkynyl, alkoxy, hydroxy, oxo (valency rules permitting),carboxy, carboxy ester, amino, alkylamino, dialkylamino, optionallysubstituted cycloalkyl, optionally substituted heterocycloalkyl,heteroaryl, optionally substituted aryl, —C(O)NR′R″ (where R′ ishydrogen or alkyl and R″ is hydrogen, alkyl, aryl, or heterocyclyl),—NR′C(O)R″ (where R′ is hydrogen or alkyl and R″ is alkyl, aryl, orheterocyclyl), and —NHS(O)₂R′ (where R′ is alkyl, aryl, or heteroaryl).

“Optionally substituted heterocyclylalkyl” means an alkyl groupsubstituted with an optionally substituted heterocyclyl group, asdefined herein. Examples include (4-methylpiperazin-1-yl) methyl,(morpholin-4-yl) methyl, (pyridin-4-yl) methyl, 2-(oxazolin-2-yl)ethyl,4-(4-methylpiperazin-1-yl)-2-butenyl, and the like. In addition, thealkyl portion of a heterocyclylalkyl group may be substituted asdescribed in the definition for “substituted”. “Lower heterocyclylalkyl”means a heterocyclylalkyl where the “alkyl” portion of the group has oneto six carbons. “Heteroalicyclylalkyl” or “lower heterocycloalkylalkyl”means a heterocyclylalkyl where the heterocyclyl portion of the group isnon-aromatic; and “heteroarylalkyl” means a heterocyclylalkyl where theheterocyclyl portion of the group contains an aromatic ring. Such termsmay be described in more than one way, for example, “lowerheterocyclylalkyl” and “heterocyclyl C₁₋₆alkyl” are equivalent terms.Additionally, for simplicity, the number of annular atoms (includingheteroatoms) in a heterocycle may be denoted as “C_(x)-C_(y)” (as in“C_(x)-C_(y)-heterocyclyl” and “C_(x)-C_(y)-heteroaryl” (and the like)),where x and y are integers. So, for example, C₅-C₁₄-heterocyclyl refersto a 5 to 14 membered ring system having at least one heteroatom and nota ring system containing 5 to 14 annular carbon atoms.

Preferred heterocyclyls include, but are not limited to, acridinyl,azocinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benzoxazolyl,benzthiazolyl, benztriazolyl, pyridotriazolyl, benzisoxazolyl,benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl,carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl,2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl,furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl,indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl,naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl,pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl,pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole,pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl,pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl,quinuclidinyl, tetrahydrofuiranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl,thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, and xanthenyl.

“Hydroxyalkyl” means an alkanyl, alkenyl, or alkynyl radical, as definedherein, substituted with at least one, preferably one, two, or three,hydroxy group(s), provided that if two hydroxy groups are present theyare not both on the same carbon atom. Representative examples include,but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl,3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl,3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl,1-(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyland 2-(hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl,2,3-dihydroxypropyl, or 1-(hydroxymethyl)-2-hydroxyethyl, and the like.

“Optional” or “optionally” means that the subsequently described eventor circumstance may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not. One of ordinary skill in the art would understand that withrespect to any molecule described as containing one or more optionalsubstituents, only sterically practical and/or synthetically feasiblecompounds are meant to be included. “Optionally substituted” refers toall subsequent modifiers in a term. So, for example, in the term“optionally substituted arylC₁₋₈ alkyl,” both the “C₁₋₈ alkyl” portionand the “aryl” portion of the molecule may or may not be substituted. Alist of exemplary optional substitutions is presented below in thedefinition of “substituted.”

“Saturated bridged ring system” refers to a bicyclic or polycyclic ringsystem that is not aromatic. Such a system may contain isolated orconjugated unsaturation, but not aromatic or heteroaromatic rings in itscore structure (but may have aromatic substitution thereon). Forexample, hexahydro-furo[3,2-b]furan, 2,3,3a,4,7,7a-hexahydro-1H-indene,7-aza-bicyclo[2.2.1]heptane, and 1,2,3,4,4a,5,8,8a-octahydro-naphthaleneare all included in the class “saturated bridged ring system.

“Spiro”, “Spirocyclyl” or “spiro ring” refers to a ring originating froma particular annular carbon of another ring. For example, as depictedbelow, a ring atom of a saturated bridged ring system (rings B and B′),but not a bridgehead atom, can be a shared atom between the saturatedbridged ring system and a spirocyclyl (ring A) attached thereto. Aspirocyclyl can be carbocyclic or heteroalicyclic.

“Substituted” alkyl, alkylene, alkylidene, and alkylidyne referrespectively to alkyl, alkylene, alkylidene, and alkylidyne where one ormore (for example up to about five, in another example, up to aboutthree) hydrogen atoms are replaced by a substituent independentlyselected from halo, optionally substituted aryl, hydroxy, alkoxy,optionally substituted heterocyclyl, alkylenedioxy, amino, alkylamino,dialkylamino), amidino, aryloxy, arylalkyloxy, carboxy, carboxy ester,alkylcarbonyloxy, carbamyl, alkylaminocarbonyl, dialkylaminocarbonyl,benzyloxycarbonylamino (CBZ-amino), cyano, acyl, nitro, S(O)_(n1)R′(where n1 is 0, 1, or 2 and R′ is alkyl, substituted alkyl, optionallysubstituted aryl, optionally substituted heterocycloalkyl, or optionallysubstituted heteroaryl), oxo, acylamino, and sulfonamido.

Table 1 depicts a representative example of the compounds of Section I.

TABLE 1

As use in one embodiment of the invention, the MEK inhibitor is selectedfrom the compounds in Table I having a MEK-binding affinity of about 4μM or less. In another embodiment, the MEK inhibitor is selected fromthe compounds in Table I having a MEK-binding affinity of about 3 μM orless. In another embodiment, the MEK inhibitor is selected from thecompounds in Table I having a MEK-binding affinity of about 2 μM orless. In another embodiment, the MEK inhibitor is selected from thecompounds in Table I having a MEK-binding affinity of about 1.6 μM orless. In another embodiment, the MEK inhibitor is selected from thecompounds in Table I having a MEK-binding affinity of about 1 μM orless. In another embodiment, the MEK inhibitor is selected from thecompounds in Table I having a MEK-binding affinity of about 0.7 μM orless. In another embodiment, the MEK inhibitor is selected from thecompounds in Table I having a MEK-binding affinity of about 0.3 μM orless. In another embodiment, the MEK inhibitor is selected from thecompounds in Table I having a MEK-binding affinity of about 0.2 μM orless. In another embodiment, the MEK inhibitor is selected from thecompounds in Table I having a MEK-binding affinity of about 0.1 μM orless.

Experimental Preparation of Compounds

Generally, the compounds listed below were identified by LC-MS, and/orisolated, and characterized by ¹H-NMR (most typically 400 MHz). Liquidchromatography-mass spectral (LC-MS) analyses were performed using atleast one of: a Hewlett-Packard Series 1100 MSD, an Agilent 1100 SeriesLC/MSD (available from Agilent Technologies Deutschland GmbH ofWaldbronn Germany), or a Waters 8-Channel MUX System (available fromWaters Corporation of Milford, Mass.). Compounds were identifiedaccording to either their observed mass [M+1] or [M+Na] ion (positivemode) or [M−1] ion (negative mode). ¹H-NMR data for compounds was takenwith a Varian AS400 Spectrometer (400 MHz, available from Varian GmbH,Darmstadt, Germany).

Starting materials and intermediates used to prepare a compound of theinvention are either commercially available or can be prepared by one ofordinary skill in the art.

Example 1I-({3,4-Difluoro-2-[(2-fluoro-4-iodophenyi)amino]phenyl}carbonyl)azetidin-3-ol

3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid (2.1 g, 5.3mmol) was taken into DMF (10 mL) followed by addition of PyBOP (2.6 g,5.3 mmol) and the mixture was allowed to stir at room temperature over15 minutes. Azetidin-3-ol hydrochloride (870 mg, 8.0 mmol) and DIPEA(1.85 mL, 11.2 mmol) was then added and the mixture was allowed to stiran additional hour at room temperature. The mixture was then partitionedwith ethyl acetate and 0.5 M aqueous sodium hydroxide solution. Theorganic layer was then washed with water (3×) then brine and dried overanhydrous sodium sulfate. Filtration and concentration followed bysilica gel flash chromatography using ethyl acetate: hexanes (5:1)eluent afforded1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol(2.09 g, 87% yield) as a colorless amorphous solid. ¹H NMR (400 MHz,CDCl₃): 8.47 (s, 1H), 7.39 (dd, 1H), 7.32 (d, 1H), 7.13-7.09 (m, 1H),6.84-6.78 (m, 1H), 6.63-6.57 (m, 1H), 4.74-4.67 (m, 1H), 4.43-4.39 (m,2H), 4.20-3.96 (br d, 2H), 2.50 (d, 1H).

Example 2 4-(2-Fluoro-4-iodo-phenylamino)-thiophene-3-carboxylic acid

A solution of methyl-4-oxo-tetrahydro-thiophene-3-carboxylate (5.75 g,35.9 mmol) and 2-fluoro-4-iodo-aniline (9.4 g, 40.9 mmol) were heated toreflux in a mixture of ethanol (25 mL) and acetic acid (0.3 mL) for 18hours. The solution was cooled to room temperature, filtered and thesolid product dried in vacuo to providemethyl-4-(2-fluoro-4-iodo-phenylamino)-2,3-dihydro-thiophene-3-carboxylate(5.70 g, 42% yield). MS (EI) for C₁₂H₁₁FINO₂S: 380 (MH⁺).

A mixture ofmethyl-4-(2-fluoro-4-iodo-phenylamino)-2,3-dihydro-thiophene-3-carboxylate(5.7 g, 15.0 mmol) and chloranil (5.7 g, 15.0 mmol) in toluene (50 mL)was heated to reflux for 2 hours. The solution was cooled to roomtemperature and the solvent was evaporated. The resulting dark brownsolid was recrystallized from methanol to provide methyl4-(2-fluoro-4-iodo-phenylamino)-thiophene-3-carboxylate (2.8 g, 49.5%yield). MS (EI) for C₁₂H₉FINO₂S: 378 (MH⁺).

Methyl 4-(2-Fluoro-4-iodo-phenylamino)-thiophene-3-carboxylate (270 mg,0.72 mmol) was dissolved in a mixture of tetrahydrofuran:methanol (6:1,3 mL) and a solution of lithium hydroxide (0.1 g, 4.2 mmol) in 1 mL ofwater was added. The solution was stirred at room temperature for 18hours and the solvent was concentrated. The residue was dissolved in 5mL of water and the solution was acidified to pH 1 with 1N HCl. Theresulting solid was filtered and dried in vacuo to provide 210 mg (79%yield) of 4-(2-fluoro-4-iodo-phenylamino)-thiophene-3-carboxylic acid.MS (EI) for C₁₁H₇FINO₂S: 364 (MH⁺).

Example 3

Using the same or analogous synthetic techniques described in examples 1and 2 and substituting with alternative reagents, the followingcompounds of the invention were prepared:

-   -   a)        1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol:        MS (EI) for C₁₆H₁₂F₃IN₂O₂: 449 (MH⁺).    -   b)        1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-one:        MS (EI) for C₁₆H₁₀F₃IN₂O₂: 447 (MH⁺).    -   c)        6-(azetidin-1-ylcarbonyl)-2,3-difluoro-N-(2-fluoro-4-iodophenyl)aniline:        MS (EI) for C₁₆H₁₂F₃IN₂O: 433 (MH⁺).    -   d)        6-[(3,3-difluoroazetidin-1-yl)carbonyl]-2,3-difluoro-N-(2-fluoro-4-iodophenyl)aniline:        MS (EI) for C₁₆H₁₀F₅IN₂O: 469 (MH⁺).    -   e)        1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(hydroxymethyl)azetidin-3-ol:        MS (EI) for C₁₇H₁₄F₃IN₂O₃: 479 (MH⁺).    -   f)        2,3-difluoro-N-(2-fluoro-4-iodophenyl)-6-([3-(methyloxy)azetidin-1-yl]carbonyl}aniline:        MS (EI) for C₁₇H₁₄F₃IN₂O₂: 463 (MH⁺).    -   g)        1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(trifluoromethyl)azetidin-3-ol:        MS (EI) for C₁₇H₁₁F₆IN₂O₂: 517 (MH⁺).    -   h)        1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-prop-2-en-1-ylazetidin-3-ol:        MS (EI) for C₁₉H₁₆F₃IN₂O₂: 489 (MH⁺).    -   i)        3-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]propane-1,2-diol:        MS (EI) for C₁₉H₁₈F₃IN₂O₄: 523 (MH⁺).    -   j)        1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-ethylazetidin-3-ol:        MS (EI) for C₁₈H₁₆F₃IN₂O₂: 477 (MH⁺).    -   k)        1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-methylazetidin-3-ol:        MS (EI) for C₁₇H₁₄F₃IN₂O₂: 463 (MH⁺).    -   l)        1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidine-2-carboxylic        acid: MS (EI) for C₁₇H₁₂F₃IN₂O₃: 477 (MH⁺).    -   m)        [1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-2-yl]methanol:        MS (EI) for C₁₇H₁₄F₃IN₂O₂: 463 (MH⁺).    -   n)        1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-ethenylazetidin-3-ol:        MS (EI) for C₁₈H₁₄F₃IN₂O₂: 475 (MH⁺).    -   o)        1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidine-3-carboxylic        acid: MS (EI) for C₁₇H₁₂F₃IN₂O₃: 477 (MH⁺).    -   p)        1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-one        oxime: MS (EI) for C₁₆H₁₁F₃IN₃O₂: 462 (MH⁺).    -   q)        [1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]methanol:        MS (EI) for C₁₇H₁₄F₃IN₂O₂: 463 (MH⁺).    -   r)        1-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]ethane-1,2-diol:        MS (EI) for C₁₈H₁₆F₃IN₂O₄: 509 (MH⁺).    -   s)        1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-amine:        MS (EI) for C₁₆H₁₃F₃IN₃O: 448 (MH⁺).    -   t)        1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidine-3-carboxamide:        MS (EI) for C₁₇H₁₃F₃IN₃O₂: 476 (MH⁺).    -   u)        1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N-hydroxyazetidine-3-carboxarnide:        MS (EI) for C₁₇H₁₃F₃IN₃Ohd 3: 492 (MH⁺).    -   v)        1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidine-2-carboxamide:        MS (EI) for C₁₇H₁₃F₃IN₃O₂: 476 (MH⁺).    -   w)        1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N-hydroxyazetidine-2-carboxamide:        MS (EI) for C₁₇H₁₃F₃IN₃O₃: 492 (MH⁺).    -   x)        N-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]methanesulfonamide:        MS (EI) for C₁₇H₁₅F₃IN₃O₃S: 526 (MH⁺).    -   y)        N-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]acetamide:        MS (EI) for C₁₈H₁₅F₃IN₃O₂: 490 (MH⁺).    -   z)        1,1-dimethylethyl[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ylcarbamate:        MS (EI) for C₂₁H₂₁F₃IN₃O₃: 548 (MH⁺).    -   aa)        1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(pyrrolidin-1-ylmethyl)azetidin-3-ol:        MS (EI) for C₂₁H₂₁F₃IN₃O₂: 532 (MH⁺).    -   bb)        3-[(diethylamino)methyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol:        MS (EI) for C₂₁H₂₃F₃IN₃Ohd 2: 534 (MH⁺).    -   cc)        1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(dimethylamino)methyl]azetidin-3-ol:        MS (EI) for C₁₉H₁₉F₃IN₃O₂: 506 (MH⁺).    -   dd)        1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N-methyl-N-prop-2-en-1-ylazetidine-3-carboxamide:        MS (EI) for C₂₁H₁₉F₃IN₃O₂: 530 (MH⁺).    -   ee)        1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N-methylazetidine-3-carboxamide:        MS (EI) for C₁₈H₁₅F₃IN₃O₂: 490 (MH⁺).    -   ff)        N-butyl-1-((3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidine-3-carboxamide:        MS (EI) for C₂₁H₂₁F₃IN₃O₂: 532 (MH⁺).    -   gg)        1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N-prop-2-en-1-ylazetidine-3-carboxamide:        MS (EI) for C₂₀H₁₇F₃IN₃O₂: 516 (MH⁺).    -   hh)        1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N-ethyl-N-(2-hydroxyethyl)azetidine-3-carboxamide:        MS (EI) for C₂₁H₂₁F₃IN₃O₃: 548 (MH⁺).    -   ii)        N-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbony])azetidin-3-yl]-2-methylpropanamide:        MS (EI) for C₂₀H₁₉F₃IN₃O₂: 518 (MH⁺).    -   jj)        N-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]formamide:        MS (EI) for C₁₇H₁₃F₃IN₃O₂: 476 (MH⁺).    -   kk)        N-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]-3,4-dihydroxybutanamide:        MS (EI) for C₂₀H₁₉F₃IN₃O₄: 550 (MH⁺).    -   ll)        methyl[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]carbamate:        MS (EI) for C₁₈H₁₅F₃IN₃O₃: 550 (MH⁺).    -   mm)        N-butyl-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-amine:        MS (EI) for C₂₀H₂₁F₃IN₃O: 504 (MH⁺).    -   nn)        1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N,N-diprop-2-en-1-ylazetidin-3-amine:        MS (EI) for C₂₂H₂₁F₃IN₃O: 528 (MH⁺).    -   oo)        1-({4-[(2-fluoro-4-iodophenyl)amino]-3-thienyl}carbonyl)azetidin-3-amine:        MS (EI) for C₁₄H₁₃FIN₃OS: 418 (MH⁺).    -   pp)        1-({4-[(2-fluoro-4-iodophenyl)amino]-3-thienyl}carbonyl)azetidin-3-ol:        MS (EI) for C₁₄H₁₂FIN₂O₂S: 419 (MH⁺).    -   qq)        1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol:        MS (EI) for C₂₁H₂₁F₃IN₃O₂: 532 (MH⁺).    -   rr)        1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2R)-piperidin-2-yl]azetidin-3-ol:        MS (EI) for C₂₁H₂₁F₃IN₃O₂: 532 (MH⁺).    -   ss)        1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[2-pyrrolidin-2-yl]azetidin-3-ol:        MS (EI) for C₂₀H₁₉F₃IN₃O₂: 518 (MH⁺).    -   tt)        3-(aminomethyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol:        MS (EI) for C₁₇H₁₅F₃IN₃O₂: 478 (MH⁺).    -   uu)        3-[1-aminoethyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)aminolphenyl}carbonyl)azetidin-3-ol:        MS (EI) for C₁₈H₁₇F₃IN₃O₂: 492 (MH⁺).    -   vv)        3-[1-aminopropyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol:        MS (EI) for C₁₉H₁₉F₃IN₃O₂: 506 (MH⁺).

Assay

For a biochemical measurement of MEK1 inhibitory activity, compounds ofthe invention were screened in a triple coupled cRaf-MEK-ERK2 assayusing ALPHASCREEN (Registered Trademark of Perkin Elmer) technology(Perkin Elmer). The compound of the invention, 0.5 μL of 100% DMSO stocksolution, is diluted into an assay buffer composed of 20 mM Tris(pH=7.5), 10 mM magnesium chloride, 0.03% CHAPS and 1 mM DTT.Subsequently, 10 μL of substrate mixture is added composed of unactiveMEK1 (3 nM), ATP (50 μM), unactive ERK2 (4 nM), biotinylated MBP peptide(b-FFKNIVTPRTPPPSQGK, 1 μM) and antiphospho MBP peptide (0.5 nM). Themixture is then gently shaken for 30 minutes at room temperaturefollowed by addition of active cRaf (5 μL at 0.5 nM) to initiatereaction. The mixture is then shaken for 100 minutes at room temperaturethen quenched by addition of 10 μL of a mixture of 5 μg/mL streptavidindonor beads and 5 μg/mL protein A acceptor beads in detection buffer (75mM Hepes pH=7.5, 300 mM sodium chloride, 120 mM EDTA, 0.3% BSA and 0.03%Tween), followed by incubation overnight and signal detection on anALPHAQuest® (Registered Trademark of Perkin Elmer) plate reader (PerkinElmer).

Section II

In one embodiment, in section II the invention provides compounds thatare useful as inhibitors of PI3K that have the Formula VI:

and optionally as a pharmaceutically acceptable salt or hydrate thereof,wherein

-   R¹ is hydrogen, optionally substituted C₁-C₆ alkyl, optionally    substituted C₃-C₇ cycloalkyl, optionally substituted aryl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl or optionally    substituted heteroarylalkyl;-   X is —NR³—;-   R² is hydrogen, optionally substituted C₁-C₆ alkyl, optionally    substituted C₃-C₇ cycloalkyl, optionally substituted aryl,    optionally substituted aryl-C₁₋₆ alkyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclyl-aryl- or optionally substituted heteroaryl;    R² is optionally further substituted with 1, 2, 3, or 4 R⁸ groups;-   R³ is hydrogen;-   R₄ is hydrogen or optionally substituted C₁-C₆ alkyl, optionally    substituted C₁-C₆ alkoxy, C₁-C₆ alkoxyalkyl, aminoalkyl, optionally    substituted C₃-C₇ cycloalkyl, optionally substituted aryl, or    optionally substituted heteroaryl;-   R⁵ is hydrogen or optionally substituted C₁-C₆ alkyl;-   R⁶ is hydrogen, halo, haloalkyl, haloalkoxy, —NR³—, optionally    substituted C₁-C₆ alkyl optionally substituted C₁-C₆ alkoxy, C₁-C₆    alkoxyalkyl, acyl, aminoalkyl, optionally substituted C₃-C₇    cycloalkyl, optionally substituted aryl, optionally substituted    aryl-C₁₋₆alkyl, optionally substituted heterocyclyl, or optionally    substituted heteroaryl; substitutable R⁶ groups are optionally    further substituted with 1, 2, 3, or 4 R⁹ groups;-   R⁸ at each occurrence is independently hydroxy, halo, haloalkyl,    haloalkoxy, optionally substituted C₁-C₆ alkyl, optionally    substituted C₁-C₆ alkoxy, C₁-C₆ alkoxyalkyl,    C₁-C₆alkoxyalkylaminoalkyl, C₁-C₆ alkylcarboxyheterocyclyl,    —O—C₁-C₆alkylheterocyclyl, aminoalkyl, optionally substituted C₃-C₇    cycloalkyl, optionally substituted aryl, optionally substituted aryl    C₁-C₆ alkyl, optionally substituted heteroalicyclic, optionally    substituted heteroalicyclicalkyl, optionally substituted heteroaryl    or optionally substituted heteroarylalkyl; and-   R⁹ at each occurrence is independently halo, haloalkyl, haloalkoxy,    optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆    alkoxy, C₁-C₆ alkoxyalkyl, C₁-C₆ carboxyalkyl, alkoxycarbonyl,    aminoalkyl, optionally substituted C₃-C₇ cycloalkyl, optionally    substituted aryl, optionally substituted aryl C₁-C₆ alkyl,    optionally substituted aryloxy, optionally substituted heterocyclyl,    or optionally substituted heteroaryl.

In one embodiment, the invention provides a PI3K inhibitor of formulaVIa:

and optionally as a pharmaceutically acceptable salt or hydrate thereof,wherein

-   R¹ is hydrogen, optionally substituted C₁-C₆ alkyl, optionally    substituted C₃-C₇ cycloalkyl, optionally substituted aryl,    optionally substituted heteroalicyclic, optionally substituted    heteroalicyclicalkyl, optionally substituted heteroaryl or    optionally substituted heteroarylalkyl;-   X is —NR³—;-   R² is hydrogen, optionally substituted C₁-C₆ alkyl, C₃-C₇    cycloalkyl, aryl, aryl-C₁₋₆alkyl, heteroalicyclic,    heterocyclylalkyl, heterocyclyl-aryl- or heteroaryl; where the    cycloalkyl, aryl, aryl-C₁₋₆ alkyl, heteroalicyclic,    heterocyclylalkyl, heterocyclyl-aryl-, and heteroaryl groups in R²    are optionally substituted with 1, 2, 3, or 4 R⁸ groups;-   R³ is hydrogen;-   R⁴ is optionally substituted C₁-C₆ alkyl;-   R⁶ is hydrogen, acyl, phenyl, heteroalicyclic, or heteroaryl; where    the phenyl, heteroalicyclic, and heteroaryl in R⁶ are optionally    substituted with 1, 2, 3, or 4 R⁹ groups;-   R⁸ at each occurrence is independently hydroxy, halo, haloalkyl,    C₁-C₆ alkyl, optionally substituted C₁-C₆ alkoxy, C₁-C₆ alkoxyalkyl,    C₁-C₆ alkoxyalkylaminoalkyl, C₁-C₆ alkylcarboxyheterocyclyl,    —O—C₁-C₆alkylheterocyclyl, aminoalkyl, optionally substituted C₃-C₇    cycloalkyl, optionally substituted aryl, optionally substituted aryl    C₁-C₆ alkyl, optionally substituted heteroalicyclic, optionally    substituted heteroalicyclicalkyl, optionally substituted heteroaryl    or optionally substituted heteroarylalkyl; and-   R⁹ at each occurrence is independently halo, haloalkyl, haloalkoxy,    C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxyalkyl, C₁-C₆ carboxyalkyl,    alkoxycarbonyl, aminoalkyl, optionally substituted C₃-C₇ cycloalkyl,    optionally substituted aryl, optionally substituted aryl C₁-C₆    alkyl, optionally substituted aryloxy, optionally substituted    heteroalicyclic, or optionally substituted heteroaryl.

In one embodiment, the invention provides a PI3K inhibitor of formulaVIb:

and optionally a pharmaceutically acceptable salt or solvate thereof,wherein

-   R¹ is hydrogen, optionally substituted C₁-C₆ alkyl, optionally    substituted C₃-C₇ cycloalkyl, optionally substituted aryl,    optionally substituted heteroalicyclic, optionally substituted    heteroalicyclicalkyl, optionally substituted heteroaryl or    optionally substituted heteroarylalkyl;-   R⁶ is phenyl, acyl, or heteroaryl wherein the phenyl and heteroaryl    are optionally substituted with 1, 2, 3, or 4 R⁹ groups; and-   R⁹ at each occurrence is independently halo, haloalkyl, haloalkoxy,    C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxyalkyl, C₁-C₆ carboxyalkyl,    alkoxycarbonyl, aminoalkyl, optionally substituted C₃-C₇ cycloalkyl,    optionally substituted aryl, optionally substituted aryl C₁-C₆    alkyl, aryloxy, optionally substituted heteroalicyclic, or    optionally substituted heteroaryl.

In another embodiment (A), the invention provides a compound of FormulaVIa where R¹ is hydrogen, C₁-C₆ optionally substituted alkyl, optionallysubstituted C₃-C₇ cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted aryl, optionally substituted heteroalicyclic,optionally substituted heteroalicyclicalkyl, optionally substitutedheteroaryl or optionally substituted heteroarylalkyl; and all othergroups are as defined in Formula VIa. In another embodiment, R¹ ishydrogen, optionally substituted alkyl, optionally substitutedcycloalkyl, or optionally substituted heteroalicyclicalkyl. In yetanother embodiment, R¹ is hydrogen, alkyl, alkyl substituted with one ortwo hydroxy, alkyl substituted with alkoxy, alkyl substituted with aryl,C₃-C₇ cycloalkyl, or heteroalicyclicalkyl. In yet another embodiment, R¹is hydrogen, methyl, ethyl, propyl, isopropyl, 2-hydroxypropyl,3-hydroxypropyl, 2-ethoxyethyl, 3-methoxypropyl, 3-ethoxypropyl,3-isopropoxypropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,benzyl, or 2-piperidin-1-ylethyl. In yet another embodiment, R¹ isethyl, isopropyl, cyclopentyl, or cyclohexyl. In yet another embodiment,R¹ is ethyl.

In another embodiment (B), the invention provides a compound of FormulaVIa where R² is hydrogen or optionally substituted C₁-C₆ alkyl; and allother groups are as defined in Formula VIa. In another embodiment, R² ishydrogen or alkyl where the alkyl is optionally substitued with one,two, or three amino, alkylamino, dialkylamino, or halo. In anotherembodiment, R² is hydrogen, methyl, ethyl, propyl, isopropyl,tert-butyl, 3-aminopropyl, 3-(N-methylamino)-propyl, or3-(N,N-dimethylamino)-propyl. In another embodiment, R² is hydrogen orethyl. In another embodiment, R² is hydrogen.

In another embodiment, the invention provides a compound of Formula VIaor VIb where R² is hydrogen and all other groups are as defined forFormula VIa or VIb, respectively.

In another embodiment, the invention provides a compound of Formula VIaor VIb where R² is optionally substituted C₁-C₆ alkyl; and all othergroups are as defined in Formula VIa or VIb, respectively. In anotherembodiment, R² is alkyl where the alkyl is optionally substitued withone, two, or three arnino, alkylamino, dialkylamino, or halo. In anotherembodiment, R² is methyl, ethyl, propyl, isopropyl, tert-butyl,3-aminopropyl, 3-(N-methylamino)-propyl, or3-(N,N-dimethylamino)-propyl. In another embodiment, R² is ethyl.

In another embodiment (C), the invention is directed to a Compound ofFormula VIa where R⁴ is optionally substituted C₁-C₆ alkyl; and allother groups are as defined in Formula VIa. In another embodiment, R⁴ ismethyl or ethyl. In another embodiment, R⁴ is methyl.

Another embodiment (D), the invention is directed to a Compound ofFormula VIa or VIb where R² is hydrogen or optionally substituted C₁-C₆alkyl and R⁶ is acyl; and all other groups are as defined in Formula VIaor VIb, respectively. In another embodiment, R⁶ is alkylcarbonyl. Inanother embodiment, R⁶ is acetyl.

Another embodiment (E), the invention is directed to a Compound ofFormula VIa or VIb where R² is hydrogen or optionally substituted C₁-C₆alkyl and R⁶ is phenyl optionally substituted with 1, 2, 3, or 4 R⁹groups; and all other groups are as defined in Formula VIa or VIb,respectively. In another embodiment, R⁶ is phenyl optionally substitutedwith one or two R⁹ groups; and R⁹ at each instance is independentlyselected from aryl, halo, alkoxy, aryloxy, alkoxycarbonyl, alkyl, andhaloalkyl. In another embodiment, R⁶ is phenyl optionally substitutedwith one or two R⁹ groups; and each R⁹ at each instance is independentlyselected from phenyl, fluoro, chloro, methoxy, phenyloxy, methyl,methoxycarbonyl, and trifluoromethyl. In another embodiment, R⁶ isphenyl, phenyl substituted with phenyl, fluorophenyl, difluorophenyl,chlorophenyl, dichlorophenyl, phenyl substituted with chloro and fluoro,methoxyphenyl, dimethoxyphenyl, phenyloxyphenyl, ortrifluoromethylphenyl. Yet even more specifically, R⁶ is phenyl,2-phenyl-phenyl, 3-phenyl-phenyl, 4-phenyl-phenyl, 2-fluorophenyl,3-fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl,2,5-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl,3,5-difluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl,2,6-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl,3-chloro-4-fluoro-phenyl, 2-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 2,3-dimethoxyphenyl, 2,4-dimethoxyphenyl,2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 3,4-dimethoxyphenyl,3,5-dimethoxyphenyl, 4-phenyloxyphenyl, 2-trifluoromethylphenyl, or3-trifluoromethylphenyl.

Another embodiment, the invention is directed to a Compound of FormulaVIa or VIb where R⁶ is phenyl subtituted with 1, 2, 3, or 4 R⁹ groups;and all other groups are as defined in Formula VIa or VIb, respectively.

Another embodiment, the invention is directed to a Compound of FormulaVIa or VIb where R⁶ is heteroaryl optionally substituted with 1, 2, 3,4, or 5 R⁹ groups; and all other groups are as defined in Formula VIa orVIb, respectively.

In another embodiment (G), the invention is directed to a Compound ofFormula VIa or VIb where R² is hydrogen or optionally substituted C₁-C₆alkyl and R⁶ is heteroaryl optionally substituted with 1, 2, 3, 4, or 5R⁹ groups; and all other groups are as defined in Formula VIa or VIb,respectively.

In another embodiment (G1), the invention is directed to a Compound ofFormula VIa or VIb where R² is hydrogen or ethyl and R⁶ is a 6-memberedheteroaryl optionally substituted with one or two R⁹; and all othergroups are as defined in Formula VIa or VIb, respectively. In anotherembodiment, R⁶ is pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl eachof which is optionally substituted with one R⁹ where R⁹ at each instanceis halo. In another embodiment, R⁶ is pyridin-2-yl, pyridin-3-yl,pyridin-4-yl, 3-fluoropyridin-4-yl, pyrazin-2-yl, pyrazin-3-yl,pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridazin-3-yl, orpyridazin-4-yl, each of which is optionally substituted with one or twoR⁹.

In another embodiment (G2), the invention is directed to a Compound ofFormula VIa or VIb where R² is hydrogen or ethyl and R⁶ is pyrazinyl,pyrimidinyl, or pyridazinyl each of which is optionally substituted withone R⁹ where R⁹ at each instance is halo; and all other groups are asdefined in Formula VIa or VIb, respectively. In another embodiment, R⁶is pyrazin-2-yl, pyrazin-3-yl, pyrimidin-2-yl, pyrimidin-4-yl,pyrimidin-5-yl, pyridazin-3-yl, or pyridazin-4-yl.

In another embodiment (G3), the invention is directed to a Compound ofFormula VIa or VIb where R² is hydrogen or ethyl and R⁶ is 5-memberedheteroaryl optionally substituted with one or two R⁹; and all othergroups are as defined in Formula VIa or VIb, respectively. In anotherembodiment R⁶ is pyrazolyl, imidazolyl, thienyl, thiazolyl, oxazolyl,isoxazolyl, oxadiazolyl, furanyl, pyrrolyl, triazolyl, or tetrazolyl,each of which is optionally substituted with one R⁹ where R⁹ at eachinstance is alkyl, arylalkyl, cyano, aryl, alkoxycarbonyl, or halo. Inanother embodiment R⁶ is pyrazolyl, thienyl, thiazolyl, oxazolyl,furanyl, or pyrrolyl, each of which is optionally substituted with oneR⁹ where R⁹ at each instance is alkyl, alkoxycarbonyl, or halo. Inanother embodiment, R⁶ is pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl,pyrazol-5-yl, thien-2-yl, thien-3-yl, thiazol-2-yl, thiazol-4-yl,thiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, furan-2-yl,furan-3-yl, pyrrol-1-yl, pyrrol-2-yl, or pyrrol-3-yl; each of which isoptionally substituted with one R⁹ where R⁹ at each instance, is methyl,N-tert-butoxycarbonyl, or chloro. In another embodiment, R⁶ ispyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, thien-2-yl, thien-3-yl,thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, oxazol-2-yl, oxazol-4-yl,oxazol-5-yl, furan-2-yl, furan-3-yl, pyrrol-2-yl, or pyrrol-3-yl; eachof which is optionally substituted with one R⁹ where R⁹, when present,is methyl, N-tert-butoxycarbonyl, or chloro.

In another embodiment (G4), the invention is directed to a Compound ofFormula VIa or VIb where R² is hydrogen or ethyl and R⁶ is thien-2-yl,thien-3-yl, pyrrol-2-yl, furan-2-yl, furan-3-yl, pyrazol-3-yl,pyrazol-4-yl, pyrazol-5-yl, thiazo]-2-yl, thiazol-5-yl, isoxazol-4-yl,imidazol-5-yl, triazol-5-yl, or tetrazol-5-yl, each of which isoptionally substituted with one R⁹ where R⁹, when present, is methyl,N-tert-butoxycarbonyl, or chloro; and all other groups are as defined inFormula VIa or VIb, respectively.

In another embodiment (G5), the invention is directed to a Compound ofFormula VIa or VIb where R² is hydrogen or ethyl and R⁶ is indolyloptionally substituted with 1, 2, 3, or 4 R⁹ groups; and all othergroups are as defined in Formula VIa or VIb, respectively. In anotherembodiment R⁶ is indol-2-yl, indol-3-yl, indol-4-yl, indol-5-yl,indol-6-yl, or indol-7-yl; each of which is optionally substituted with1, 2, 3, or 4 R⁹ groups. In another embodiment, R⁶ is indol-6-yl.

In another embodiment of the Invention (H), the invention is directed toa Compound of Formula VIa where R¹ is hydrogen, optionally substitutedC₁-C₆ alkyl, optionally substituted C₃-C₇ cycloalkyl, or optionallysubstituted heteroalicyclicalkyl; R² is hydrogen or C₁-C₆ alkyloptionally substituted with amino, alkylamino, dialkylamino, or halo; R⁴is alkyl; R⁶ is phenyl or heteroaryl wherein the phenyl and heteroarylare optionally substituted with one, two, or three R⁹ groups; and eachR⁹, when present, is independently alkyl, arylalkyl, cyano, aryl,alkoxycarbonyl, or halo.

In another embodiment of the Invention (J), the invention is directed toa Compound of Formula VIa where R² is hydrogen or ethyl, R⁴ is methyl,and R⁶ is pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, thien-2-y],thien-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, oxazol-2-yl,oxazol-4-yl, oxazol-5-yl, furan-2-yl, furan-3-yl, pyrrol-2-yl, orpyrrol-3-yl; each of which is optionally substituted with 1, 2, 3, 4, or5 R⁹ groups; and all other groups are as defined in Formula VIa.

In another embodiment of the Invention (K), the invention is directed toa Compound of Formula VIa where R¹ is alkyl or cycloalkyl; R⁴ is methyl;and R⁶ is heteroaryl optionally substituted with one or two R⁹ groups;and all other groups are as defined in Formula VIa. In anotherembodiment, each R⁹, when present, is independently alkyl,alkoxycarbonyl, or halo. In another embodiment, R⁶ is pyrazol-3-yl,pyrazol-4-yl, pyrazol-5-yl, thien-2-yl, thien-3-yl, thiazol-2-yl,thiazol-4-yl, thiazol-5-yl, oxazol-2-yl, oxazol-4-yl,oxazol-5-yl,furan-2-yl, furan-3-yl, pyrrol-2-yl, or pyrrol-3-yl; each ofwhich is optionally substituted with one R⁹ where R⁹, when present, ismethyl or N-tert-butoxycarbonyl.

In another embodiment (K1) of embodiment K, the invention is directed toa Compound of Formula VIa where R² is hydrogen; and all other groups areas defined in Embodiment K.

In another embodiment (K2) of embodiment K, the invention is directed toa Compound of Formula VIa where R² is methyl or ethyl; and all othergroups are as defined in Embodiment K.

In another embodiment (L), the invention is directed to a Compound ofFormula VIa where R¹ is alkyl or cycloalkyl; R⁴ is methyl; and R⁶ isphenyl optionally substituted with one or two R⁹ groups; and all othergroups are as defined in Formula VIa. In another embodiment, each R⁹,when present, is independently halo, alkoxy, or haloalkyl.

In another embodiment (M), the invention is directed to a Compound ofFormula VIa where R¹ is alkyl or cycloalkyl; R⁴ is methyl; and R² ishydrogen; and all other groups are as defined in Formula VIa.

In another embodiment (N), the invention is directed to a Compound ofFormula VIa where R¹ is alkyl or cycloalkyl; R⁴ is methyl; and R² isoptionally subtituted alkyl; and all other groups are as defined inFormula VIa.

In another embodiment, the invention is directed to a Compound ofFormula VII:

-   R¹ is hydrogen, optionally substituted C₁-C₆ alkyl, optionally    substituted C₃-C₇ cycloalkyl, optionally substituted aryl,    optionally substituted heteroalicyclic, optionally substituted    heteroalicyclicalkyl, optionally substituted heteroaryl or    optionally substituted heteroarylalkyl;-   X is —NR³—;-   R³ is hydrogen;-   R⁴ is optionally substituted C₁-C₆ alkyl;-   R⁵ is hydrogen;-   R⁶ is acyl and R² is heterocyclyl-aryl- optionally substituted with    1, 2, 3, or 4 R⁸ groups; or-   R⁶ is halo and R² is optionally substituted C₁-C₆ alkyl, C₃-C₇    cycloalkyl, phenyl, aryl-C₁₋₆ alkyl, heteroalicyclicalkyl, or    heterocyclyl-aryl-; where the C₃-C₇ cycloalkyl, phenyl, phenyl,    aryl-C₁₋₆ alkyl, heteroalicyclicalkyl, and heterocyclyl-aryl- groups    in R² are optionally substituted with 1, 2, 3, or 4 R⁸ groups; or-   R⁶ is phenyl optionally substituted with 1, 2, or 3 halo; and R² is    phenyl or heterocyclyl-aryl-;

where the phenyl and heterocyclyl-aryl- groups in R² are optionallysubstituted with 1, 2, 3, or 4 R⁸ groups; or

-   R⁶ is heteroaryl optionally substituted with 1, 2, or 3 halo; and R²    is heterocyclyl-aryl-optionally substituted with 1, 2, 3, 4, or 5 R⁸    groups;-   each R⁸ at each instance is independently hydroxy, halo, C₁-C₆    alkyl, haloalkyl, optionally substituted C₁-C₆ alkoxy, C₁-C₆    alkoxyalkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkoxyalkylaminoalkyl,    —O—C₁-C₆alkylheterocyclyl, aminoalkyl, optionally substituted C₃-C₇    cycloalkyl, optionally substituted aryl, optionally substituted aryl    C₁-C₆ alkyl, optionally substituted heteroalicyclic, optionally    substituted heteroalicyclicalkyl, optionally substituted heteroaryl    or optionally substituted heteroarylalkyl.

In another embodiment (A), the invention is directed to a Compound ofFormula VII where R¹ is hydrogen, optionally substituted C₁-C₆ alkyl,optionally substituted C₃-C₇ cycloalkyl, optionally substituted aryl,optionally substituted heteroalicyclic, optionally substitutedheteroalicyclicalkyl, optionally substituted heteroaryl or optionallysubstituted heteroarylalkyl; and all other groups are as defined inFormula VII. In another embodiment, R¹ is hydrogen, optionallysubstituted C₁-C₆ alkyl, or optionally substituted C₃-C₇ cycloalkyl. Inanother embodiment, R¹ is C₁-C₆ alkyl or C₃-C₇ cycloalkyl. In anotherembodiment, R¹ is methyl, ethyl, propyl, isopropyl, cyclopropyl,cyclobutyl, cyclopentyl, or cyclohexyl. In another embodiment, R¹ isethyl, isopropyl, or cyclopentyl.

In another embodiment (B), the invention is directed to a Compound ofFormula VII where R⁴ is optionally substituted C₁-C₆ alkyl; and allother groups are as defined in Formula VII. In another embodiment, R⁴ ismethyl or ethyl. In another embodiment, R⁴ is methyl.

In another embodiment (C), the invention is directed to a Compound ofFormula VII where R⁶ is acyl and R² is heterocyclyl-aryl- optionallysubstituted with 1, 2, 3, or 4 R⁸ groups; and all other groups are asdefined in Formula VII. In another embodiment, R⁶ is alkylcarbonyl. Inanother embodiment, R⁶ is acetyl.

In another embodiment of embodiment C, the invention is directed to aCompound of Formula VII where R⁶ is acyl and R² isheteroalicyclic-phenyl- optionally substituted with 1, 2, 3, or 4 R⁸groups; and all other groups are as defined in Formula VII. In anotherembodiment, R⁸, when R⁸ is present, is C₁-C₆ alkyl, C₁-C₆alkoxycarbonyl, or aryl C₁-C₆ alkyl. In another embodiment, R² ispiperazinyl-phenyl- where the piperazinyl is optionally substituted withone R⁸ where R⁸, when present, is methyl, ethyl, isopropyl,tert-butoxycarbonyl, or benzyl. In another embodiment, R² ispiperazinyl-phenyl- where the piperazinyl is optionally substituted withC₁-C₆ alkyl.

In another embodiment (E), the invention is directed to a Compound ofFormula VII where R⁶ is phenyl optionally substituted with 1, 2, 3, or 4R⁹ groups; and R² is phenyl or heterocyclyl-aryl-; where the phenyl andheterocyclyl-aryl- groups in R² are optionally substituted with 1, 2, 3,or 4 R⁸ groups; and all other groups are as defined in Formula VII. Inanother embodiment, R⁶ is phenyl, phenyl substituted with one or twohalo. In another embodiment, R⁶ is phenyl, fluorophenyl, difluorophenyl,chlorophenyl, or dichlorophenyl. In another embodiment, R⁶ is phenyl,2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl,2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl,3,4-difluorophenyl, or 3,5-difluorophenyl.

In another embodiment (E1) of Embodiment E, the invention is directed toa Compound of Formula VII where R² is phenyl or heteroalicyclic-phenyl-;where the phenyl and heteroalicyclic-phenyl- groups in R² are optionallysubstituted with 1, 2, 3, or 4 R⁸ groups; and all other groups are asdefined in Embodiment E.

In another embodiment of embodiment E1, the invention is directed to aCompound of Formula VII where R² is phenyl or heteroalicyclic-phenyl-;where the phenyl and heteroalicyclic-phenyl- groups in R² are optionallysubstituted with one or two R⁸ where each R⁸, when present, isindependently hydroxy, C₁-C₆ alkyl, optionally substituted C₁-C₆ alkoxy,alkoxycarbonyl, or —O—C₁-C₆alkylheteroalicyclic; and all other groupsare as defined in Embodiment E1.

In another embodiment of embodiment E1, R² is phenyl or phenylsubstituted with one or two R⁸ where each R⁸, when R⁸ is present, isindependently hydroxy, —O—C₁-C₆alkylheteroalicyclic, or C₁-C₆ alkoxywhere the C₁-C₆ alkoxy is optionally substituted with amino, alkylaminoor dialkylamino; and all other groups are as defined in Embodiment E1.In another embodiment, R² is phenyl, hydroxyphenyl,[(2-aminoethyl)-oxy]-phenyl, [(2-alkylamino-ethyl)-oxy]-phenyl,[(2-dialkylamino-ethyl)-oxy]-phenyl, (morpholinylalkyloxy)-phenyl,(piperidinylalkyloxy)-phenyl, (piperazinylalkyloxy)-phenyl,(N-alkyl-piperazinylalkyloxy)-phenyl, or(N-benzylpiperazinylalkyloxy)-phenyl. In another embodiment, R² ishydroxyphenyl, [(2-aminoethyl)-oxy]-phenyl,[(2-alkylamino-ethyl)-oxy]-phenyl, [(2-dialkylamino-ethyl)-oxy]-phenyl,(morpholinylalkyloxy)-phenyl, (piperidinylalkyloxy)-phenyl,(piperazinylalkyloxy)-phenyl, (N-alkyl-piperazinylalkyloxy)-phenyl, or(N-benzylpiperazinylalkyloxy)-phenyl. In another embodiment,2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl,4-[(2-dimethylamino-ethyl)-oxy]-phenyl,4-[2-(morpholin-4-yl)-ethyloxy]-phenyl,4-[2-(piperidinyl)-ethyloxy]-phenyl,4-[2-(piperazin-4-yl)-ethyloxy]-phenyl,4-[2-(N-methyl-piperazin-4-yl)-ethyloxy]-phenyl, or4-[2-(N-ethyl-piperazin-4-yl)-ethyloxy]-phenyl.

In another embodiment of embodiment E1, R² is piperazinyl-phenyl- wherethe piperazinyl is optionally substituted with one R⁸ where R⁸, whenpresent, is alkyl; and all other groups are as defined in Embodiment E1.In another embodiment, R² is morpholinylphenyl, piperazinylphenyl, or(N-alkyl-piperazinyl)-phenyl. In another embodiment, R² is4-morpholin-4-ylphenyl, 4-piperazin-4-ylphenyl,4-(N-methyl-piperazin-4-yl)-phenyl, or4-(N-ethyl-piperazin-4-yl)-phenyl.

In another embodiment (F), the invention is directed to a Compound ofFormula VII where R⁶ is heteroaryl optionally substituted with 1, 2, or3 halo; and R² is heterocyclyl-aryl- optionally substituted with 1, 2,3, 4, or 5 R⁸ groups.

In another embodiment (F1) of embodiment F, the invention is directed toa Compound of Formula VII where R⁶ is a 5-membered heteroaryl optionallysubstituted with one or two halo; R² is heteroalicyclic-phenyl- wherethe heteroalicyclic and phenyl portions of R² are independentlyoptionally substituted with one R⁸ where R⁸, when R⁸ is present is C₁-C₆alkyl or aryl C₁-C₆ alkyl; and all other groups are as defined inembodiment F.

In another embodiment (F2) of embodiment F, the invention is directed toa Compound of Formula VII where R⁶ is pyrazolyl, thienyl, thiazolyl,oxazolyl, furanyl, or pyrrolyl, each of which is optionally substitutedwith one or two halo. In another embodiment, R⁶ is pyrazol-1-yl,pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, thien-2-yl, thien-3-yl,thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, oxazol-2-yl, oxazol-4-yl,oxazol-5-yl, furan-2-yl, or furan-3-yl; each of which is optionallysubstituted with one chloro. In another embodiment, R⁶ is pyrazol-3-yl,pyrazol-4-yl, pyrazol-5-yl, thien-2-yl, thien-3-yl, thiazol-2-yl,thiazol-4-yl, thiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl,furan-2-yl, or furan-3-yl.

In another embodiment (G), the invention is directed to a Compound ofFormula VII where R⁶ is halo and R² is optionally substituted C₁-C₆alkyl, C₃-C₇ cycloalkyl, phenyl, aryl-C₁₋₆ alkyl, heteroalicyclicalkyl,or heterocyclyl-aryl-; where the C₃-C₇ cycloalkyl, phenyl, phenyl,aryl-C₁₋₆ alkyl, heteroalicyclicalkyl, and heterocyclyl-aryl- groups inR² are optionally substituted with 1, 2, 3, or 4 R⁸ groups. In anotherembodiment, R⁶ is bromo and R² is C₃-C₇ cycloalkyl, C₁-C₆ alkyloptionally substituted with heteroalicyclic, dialkylamino, phenylsubstituted with one or two halo, or heteroalicyclic-phenyl-; where theheteroalicyclic-phenyl- is optionally substituted with one or two R⁸selected from C₁-C₆ alkyl and phenyl-C₁₋₆ alkyl. In another embodiment,R² is cyclopentyl, cyclohexyl, 2-(morpholinyl)-ethyl,3-(morpholinyl)-propyl, 3-(dimethylamino)-propyl, 2-fluorophenyl,3-fluorophenyl, 4-fluorophenyl, 4-[4-methyl-piperazinyl]-phenyl,4-[4-ethyl-piperazinyl]-phenyl, 4-[4-benzyl-piperazinyl]-phenyl, or4-(morpholinyl)-phenyl.

In another embodiment (H), the invention is directed to a Compound ofFormula VII where R¹ is C₁-C₆ alkyl or C₃-C₇ cycloalkyl; R⁴ is methyl;and R⁶ is heteroaryl. In another embodiment, R⁶ is pyrazol-3-yl,pyrazol-4-yl, pyrazol-5-yl, thien-2-yl, thien-3-yl, thiazol-2-yl,thiazol-4-yl, thiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl,furan-2-yl, or furan-3-yl.

In another embodiment (J), the invention is directed to a Compound ofFormula VII where R¹ is C₁-C₆ alkyl or C₃-C₇ cycloalkyl; R⁴ is methyl;R⁵ is hydrogenand R⁶ is phenyl optionally substituted with 1, 2, or 3halo.

In another embodiment (M), the invention is directed to a Compound ofFormula VII where R⁶ is pyrazol-3-yl, pyrazol-4-yl,pyrazol-5-yl,thien-2-yl, thien-3-yl, thiazol-2-yl, thiazol-4-yl,thiazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, furan-2-yl, orfuran-3-yl.

Another aspect of the invention is a pharmaceutical compositioncomprising a compound of formula VI, VIa, VIb or VII, or apharmaceutically acceptable salt or solvate thereof, in combination witha compound of formula I, Ia, Ic, Id, II, III, IV, or V and apharmaceutically acceptable carrier.

Another aspect of the invention is a method of inhibiting the in vivoactivity of PI3Kα, and MEK the method comprising administering to asubject an effective PI3Kα-inhibiting amount of a compound of formulaVI, VIa, VIb or VII, or a pharmaceutically acceptable salt or solvatethereof, in combination with a compound of formula I, Ia, Ic, Id, II,III, IV, or V or a pharmaceutical composition thereof.

Another aspect of the invention is a method of treating diseases ordisorders associated with uncontrolled, abnormal, and/or unwantedcellular activities effected directly or indirectly by PI3Kα and MEK,the method comprising administering to a mammal (preferably human) inneed thereof a therapeutically effective amount of a compound of any offormula VI, VIa, VIb or VII, or a pharmaceutically acceptable salt orsolvate thereof, in combination with a compound of formula I, Ia, Ic,Id, II, III, IV, or V or a pharmaceutical composition thereof. Inanother embodiment, the MEK Compound is of Formula Ia and the PI3KCompound is of Formula VIa. In another embodiment, the MEK Compound isof Formula Ia and the PI3K Compound is of Formula VIb. In anotherembodiment, the MEK Compound is of Formula V and the PI3K Compound is ofFormula VIa or VIb. In another embodiment, the MEK Compound is ofSection I, Embodiment G and the PI3K Compound is of a compound fromSection II, Formula VIa or VIb, Embodiment E. In another embodiment, theMEK Compound is of Section I, Embodiment G and the PI3K Compound is of acompound of Section II, Formula VIa or VIb, Embodiment G or G3. Inanother embodiment, the MEK Compound is of Formula Ia and the PI3KCompound is of Formula VII. In another embodiment, the MEK Compound isof Formula V and the PI3K Compound is of Formula VII. In anotherembodiment, the MEK Compound is of Section I, Embodiment G and the PI3KCompound is of a compound from Section II, Formula VII, Embodiment E. Inanother embodiment, the MEK Compound is of Section I, Embodiment G andthe PI3K Compound is of a compound of Section II, Formula VI, EmbodimentF1 or F2. In another embodiment, the MEK Compound is of Section I, Table1 and the PI3K Compound is of Formula VI, VIa, VIb or VII.

Another aspect of the invention is a method of inhibiting proliferativeactivity in a cell, the method comprising administering to a cell or aplurality of cells an effective amount of a compound of formula VI, VIa,VIb or VII, or a pharmaceutically acceptable salt or solvate thereof, incombination with a compound of formula I, Ia, Ic, Id, II, III, IV, or Vor pharmaceutical composition thereof.

A further aspect of the invention is a method of treating malignanciessuch as melanoma, ovarian cancer, cervical cancer, breast cancer,colorectal cancer, and glioblastomas, among others, in a patient in needof such treatment, by administering a compound or salt of formula VI,VIa, VIb or VII, or a pharmaceutically acceptable salt or solvatethereof, in combination with a compound of formula I, Ia, Ic, Id, II,III, IV, or V or a pharmaceutical composition thereof.

Section II Definitions

As used in the present specification, the following words and phrasesare generally intended to have the meanings as set forth below, exceptto the extent that the context in which they are used indicatesotherwise or they are expressly defined to mean something different.

The symbol “—” means a single bond, “═” means a double bond, “≡” means atriple bond,

means a single or double bond. The symbol

to a group on a double-bond as occupying either position on the terminusof a double bond to which the symbol is attached; that is, the geometry,E- or Z-, of the double bond is ambiguous. When a group is depictedremoved from its parent formula, the

symbol will be used at the end of the bond which was theoreticallycleaved in order to separate the group from its parent structuralformula.

When chemical structures are depicted or described, unless explicitlystated otherwise, all carbons are assumed to have hydrogen substitutionto conform to a valence of four. For example, in the structure on theleft-hand side of the schematic below there are nine hydrogens implied.The nine hydrogens are depicted in the right-hand structure. Sometimes aparticular atom in a structure is described in textual formula as havinga hydrogen or hydrogens as substitution (expressly defined hydrogen),for example, —CH₂CH₂—. It is understood by one of ordinary skill in theart that the aforementioned descriptive techniques are common in thechemical arts to provide brevity and simplicity to description ofotherwise complex structures.

If a group “R” is depicted as “floating” on a ring system, as forexample in the formula:

then, unless otherwise defined, a substituent “R” may reside on any atomof the ring system, assuming replacement of a depicted, implied, orexpressly defined hydrogen from one of the ring atoms, so long as astable structure is formed.

If a group “R” is depicted as floating on a fused ring system, as forexample in the formulae:

then, unless otherwise defined, a substituent “R” may reside on any atomof the fused ring system, assuming replacement of a depicted hydrogen(for example the —NH— in the formula above), implied hydrogen (forexample as in the formula above, where the hydrogens are not shown butunderstood to be present), or expressly defined hydrogen (for examplewhere in the formula above, “X” equals ═CH—) from one of the ring atoms,so long as a stable structure is formed. In the example depicted, the“R” group may reside on either the 5-membered or the 6-membered ring ofthe fused ring system. In the formula depicted above, when y is 2 forexample, then the two “R's” may reside on any two atoms of the ringsystem, again assuming each replaces a depicted, implied, or expresslydefined hydrogen on the ring.

When a group “R” is depicted as existing on a ring system containingsaturated carbons, as for example in the formula:

where, in this example, “y” can be more than one, assuming each replacesa currently depicted, implied, or expressly defined hydrogen on thering; then, unless otherwise defined, where the resulting structure isstable, two “R's” may reside on the same carbon. A simple example iswhen R is a methyl group; there can exist a geminal dimethyl on a carbonof the depicted ring (an “annular” carbon). In another example, two R'son the same carbon, including that carbon, may form a ring, thuscreating a spirocyclic ring (a “spirocyclyl” group) structure with thedepicted ring as for example in the formula:

“Alkyl” is intended to include linear or branched hydrocarbon structuresand combinations thereof, inclusively. For example, “C₈ alkyl” may referto an n-octyl, iso-ctyl, and the like. Lower alkyl refers to alkylgroups of from one to six carbon atoms. Examples of lower alkyl groupsinclude methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-utyl,isobutyl, pentyl, and the like. Higher alkyl refers to alkyl groupscontaining more that eight carbon atoms. A “C₀” alkyl (as in“C₀-C₆-alkyl”) is a covalent bond. Exemplary alkyl groups are those ofC₂₀ or below. In this application, alkyl refers to alkanyl, alkenyl, andalkynyl residues (and combinations thereof); it is intended to includevinyl, allyl, isoprenyl, and the like. Thus when an alkyl residue havinga specific number of carbons is named, all geometric isomers having thatnumber of carbons are intended to be encompassed; thus, for example,either “butyl” or “C₄ alkyl” is meant to include n-butyl, sec-butyl,isobutyl, t-butyl, isobutenyl and but-2-ynyl groups; and for example,“propyl” or “C₃ alkyl” each include n-propyl, propenyl, and isopropyl.

“Cycloalkyl” means a cyclic hydrocarbon groups of from three to thirteencarbon atoms. Examples of cycloalkyl groups include c-propyl, c-butyl,c-pentyl, norbornyl, adamantyl and the like.

“Alkoxy” or “alkoxyl” refers to the group —O-alkyl, for exampleincluding from one to eight carbon atoms of a straight, branched, cyclicconfiguration, unsaturated chains, and combinations thereof attached tothe parent structure through an oxygen atom. Examples include methoxy,ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like.Lower-alkoxy refers to groups containing one to six carbons.

“Optionally substituted alkoxy” refers to the group —OR where R isoptionally substituted alkyl, as defined herein. One exemplarysubstituted alkoxy group is “polyalkoxy” or —O-optionally substitutedalkylene-optionally substituted alkoxy, and includes groups such as—OCH₂CH₂OCH₃, and glycol ethers such as polyethyleneglycol and—O(CH₂CH₂O)_(x)CH₃, where x is an integer of between about two and abouttwenty, in another example, between about two and about ten, and in afurther example between about two and about five. Another exemplarysubstituted alkoxy group is hydroxyalkoxy or —OCH₂(CH₂)_(y)OH, where yis for example an integer of between about one and about ten, in anotherexample y is an integer of between about one and about four.

“Acyl” refers to groups of from one to ten carbon atoms of a straight,branched, cyclic configuration, saturated, unsaturated and aromatic andcombinations thereof, attached to the parent structure through acarbonyl functionality. One or more carbons in the acyl residue may bereplaced by nitrogen, oxygen or sulfur as long as the point ofattachment to the parent remains at the carbonyl. Examples includeacetyl, benzoyl, propionyl, isobutyryl, t-butoxycarbonyl,benzyloxycarbonyl and the like. Lower-acyl refers to groups containingone to six carbons.

“Acyloxy” means an —OR group where R is acyl as defined herein.

“Acylamino” means an —NHR group where R is acyl as defined herein.

“Amino” refers to the group —NH₂. “Substituted amino,” refers to thegroup —N(H)R or —(R)R where each R is independently selected from thegroup: optionally substituted alkyl, optionally substituted alkoxy,optionally substituted aryl, optionally substituted heterocyclyl, acyl,carboxy, alkoxycarbonyl, sulfanyl, sulfinyl and sulfonyl, for example,diethylamino, methylsulfonylamino, and furanyl-oxy-sulfonamino.

“Aryl” refers to aromatic six- to fourteen-membered carbocyclic ring,for example, benzene, naphthalene, indane, tetralin, fluorene and thelike, univalent substituents. As univalent substituents, theaforementioned ring examples are named, phenyl, naphthyl, indanyl,tetralinyl, and fluorenyl.

“Arylalkyl” refers to a residue in which an aryl moiety is attached to aparent structure via one of an alkylene, alkylidene, or alkylidynegroup. Examples include benzyl, phenethyl, phenylvinyl, phenylallyl andthe like. Both the aryl and the corresponding alkylene, alkylidene, oralkylidyne group portion of an arylalkyl group may be optionallysubstituted. “Lower arylalkyl” refers to an arylalkyl where the “alkyl”portion of the group has one to six carbons; this can also be referredto as C₁₋₆ arylalkyl.

In some examples, as appreciated by one of ordinary skill in the art,two adjacent groups on an aromatic system may be fused together to forma ring structure. The fused ring structure may contain heteroatoms andmay be optionally substituted with one or more groups. It shouldadditionally be noted that saturated carbons of such fused groups (i.e.saturated ring structures) can contain two substitution groups.

“Halogen” or “halo” refers to fluorine, chlorine, bromine or iodine.

“Haloalkyl” and “haloaryl” refer generically to alkyl and aryl groupsthat are substituted with one or more halogens, respectively. Thus,“dihaloaryl,” “dihaloalkyl,” “trihaloaryl” etc. refer to aryl and alkylsubstituted with a plurality of halogens, but not necessarily aplurality of the same halogen; thus 4-chloro-3-fluorophenyl is withinthe scope of dihaloaryl. Haloalkyl includes, for instance, mono- toper-haloC₁-C₆ alkyl.

“Heteroatom” refers to O, S, N, or P.

“Heterocyclyl” refers to a stable three- to fifteen-membered ringsubstituent that consists of carbon atoms and from one to fiveheteroatoms selected from the group consisting of nitrogen, phosphorus,oxygen and sulfur. For purposes of this invention, the heterocyclylsubstituent may be a monocyclic, bicyclic or tricyclic ring system,which may include fused or bridged ring systems as well as spirocyclicsystems; and the nitrogen, phosphorus, carbon or sulfur atoms in theheterocyclyl group may be optionally oxidized to various oxidationstates. In a specific example, the group —S(O)₀₋₂—, refers to —S—(sulfide), —S(O)— (sulfoxide), and —SO₂— (sulfone). For convenience,nitrogens, particularly but not exclusively, those defined as annulararomatic nitrogens, are meant to include their corresponding N-oxideform, although not explicitly defined as such in a particular example.Thus, for a compound of the invention having, for example, a pyridylring; the corresponding pyridyl-N-oxide is meant to be included asanother compound of the invention. In addition, annular nitrogen atomsmay be optionally quaternized; and the ring substituent may be partiallyor fully saturated or aromatic. Examples of heterocyclyl groups include,but are not limited to, azetidinyl, acridinyl, benzodioxolyl,benzodioxanyl, benzofuranyl, carbazoyl, cinnolinyl, dioxolanyl,indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl,phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl,quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazoyl,tetrahydroisoquinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl,4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl,imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl,oxazolidinyl, triazolyl, isoxazolyl, isoxazolidinyl, morpholinyl,thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl,isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl,octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl,decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl,benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl,thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide,thiamorpholinyl sulfone, dioxaphospholanyl, and oxadiazolyl.

“Heteroalicyclic” refers specifically to a non-aromatic heterocyclylgroup. A heteroalicyclic may contain unsaturation, but is not aromatic.

“Heteroalicyclicalkyl” refers specifically to an alkyl group substitutedwith one or two non-aromatic heterocyclyl group. The heteroalicyclicring portion of this group may contain unsaturation, but is notaromatic.

“Heteroaryl” refers specifically to an aromatic heterocyclyl group.

“Heterocyclylalkyl” refers to a residue in which a heterocyclyl isattached to a parent structure via one of an alkylene, alkylidene, oralkylidyne group. Examples include (4-methylpiperazin-1-yl) methyl,(morpholin-4-yl) methyl, (pyridine-4-yl) methyl, 2-(oxazolin-2-yl)ethyl, 4-(4-methylpiperazin-1-yl)-2-butenyl, and the like. Both theheterocyclyl and the corresponding alkylene, alkylidene, or alkylidyneportion of a heterocyclylalkyl group may be optionally substituted.“Lower heterocyclylalkyl” refers to a heterocyclylalkyl where the“alkyl” portion of the group has one to six carbons.“Heteroalicyclylalkyl” refers specifically to a heterocyclylalkyl wherethe heterocyclyl portion of the group is non-aromatic; and“heteroarylalkyl” refers specifically to a heterocyclylalkyl where theheterocyclyl portion of the group is aromatic Such terms may bedescribed in more than one way, for example, “lower heterocyclylalkyl”and “heterocyclyl C₁₋₆alkyl” are equivalent terms. Additionally, forsimplicity, the number of annular atoms (including heteroatoms) in aheterocycle may be denoted as “C_(x)-C_(y)” (as in“C_(x)-C_(y)-heterocyclyl” and “C_(x)-C_(y)-heteroaryl” (and the like)),where x and y are integers. So, for example, C₅-C₁₄-heterocyclyl refersto a 5 to 14 membered ring system having at least one heteroatom and nota ring system containing 5 to 14 annular carbon atoms.

Preferred heterocyclyls and heteroaryls include, but are not limited to,acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiophenyl,benzoxazolyl, benzthiazolyl, benztriazolyl, pyridotriazolyl,benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl,4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl,decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl,isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl,isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl,pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl,pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole,pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl,pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl,quinuclidinyl, tetrahydrofiranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl,thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, and xanthenyl.

“Heterocyclyl-aryl-” means an aryl group substituted with at least one,specifically 1 or 2 heterocyclyl, as defined herein. “Optionallysubstituted heterocyclyl-aryl-” means that either or both the aryl andthe heterocyclyl can be substituted as defined in “substituted.”

“Optional” or “optionally” means that the subsequently described eventor circumstance may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not. One of ordinary skill in the art would understand that withrespect to any molecule described as containing one or more optionalsubstituents, only sterically practical and/or synthetically feasiblecompounds are meant to be included. “Optionally substituted” refers toall subsequent modifiers in a term. So, for example, in the term“optionally substituted arylC₁₋₈ alkyl,” optional substitution may occuron both the “C₁₋₈ alkyl” portion and the “aryl” portion of the moleculemay or may not be substituted. A list of exemplary optionalsubstitutions is presented below in the definition of “substituted.”

“Saturated bridged ring system” refers to a bicyclic or polycyclic ringsystem that is not aromatic. Such a system may contain isolated orconjugated unsaturation, but not aromatic or heteroaromatic rings in itscore structure (but may have aromatic substitution thereon). Forexample, hexahydro-furo[3,2-b]furan, 2,3,3a,4,7,7a-hexahydro-1H-indene,7-aza-bicyclo[2.2.1]heptane, and 1,2,3,4,4a,5,8,8a-octahydro-naphthaleneare all included in the class “saturated bridged ring system.

“Spirocyclyl” or “spirocyclic ring” refers to a ring originating from aparticular annular carbon of another ring. For example, as depictedbelow, a ring atom of a saturated bridged ring system (rings B and B′),but not a bridgehead atom, can be a shared atom between the saturatedbridged ring system and a spirocyclyl (ring A) attached thereto. Aspirocyclyl can be carbocyclic or heteroalicyclic.

“Substituted” alkyl, cycloalkyl, aryl, and heterocyclyl (includingheteroalicyclic and heteroaryl), refer respectively to alkyl, aryl, andheterocyclyl, where one or more (for example up to about five, inanother example, up to about three) hydrogen atoms are replaced by asubstituent. The substituent(s) on alkyl, aryl, heteroaryl, andheterocyclyl (including when any of these groups are part of anothergroup, such as the alkyl portion of alkoxy, or the aryl portion ofaryloxy) include, for instance, one or more groups selected fromalkylenedioxy (for example methylenedioxy), aryloxy (for example,phenoxy), carboxy, acyloxy, acylamino, benzyloxycarbonylamino, acyl,carbamyl, oxo, hydroxy, halo, nitro, cyano, 'O—C₁-C₆ alkyl, haloalkyl,C₁-C₆ alkyl, cycloalkyl, —C(O)O—C₁-C₆ alkyl, —O—C₁-C₆ alkyl-aryl, —C₁-C₆alkyl-aryl, —O—C₁-C₆ alkyl-O—C₁-C₆ alkyl, —N(R^(a))(R^(b)),(R^(a))(R^(b))N—C₁-C₆ alkyl-, —O—C₁-C₆ alkyl-N(R^(a))(R^(b)), —O—C₁-C₆alkyl-heterocyclyl, C₀-C₆ alkyl-heterocyclyl, C₀-C₆ alkyl-aryl, C₀-C₆alkyl-heteroaryl, —C(O)N(R^(a))—C₁-C₆-alkyl-N(R^(a))(R^(b)), sulfanyl,sulfinyl, sulfonyl, aryl, heteroaryl, heterocyclyl, arylalkyl-,heteroarylalkyl-, and heterocyclylalkyl, where R^(a) and R^(b) areindependently hydrogen or alkyl, or R^(a) and R^(b) together with thenitrogen to which they are attached form a heterocyclyl group. Examplesof heterocyclyl groups formed by R^(a) and R^(b) include morpholinyl andpiperazinyl. Each substituent of a substituted group is optionallysubstituted, but these optional substituents themselves are not furthersubstituted. Thus, an optionally substituted moiety is one that may ormay not have one or more substituents, and each of the substituents mayor may not have one or more substituents. But, the substituents of thesubstituents may not be substituted.

“Sulfanyl” refers to the groups: —S-(optionally substituted alkyl),—S-(optionally substituted aryl), and —S-(optionally substitutedheterocyclyl).

“Sulfinyl” refers to the groups: —S(O)—H, —S(O)-(optionally substitutedalkyl), —S(O)-optionally substituted aryl), and —S(O)-(optionallysubstituted heterocyclyl).

“Sulfonyl” refers to the groups: —S(O₂)—H, —S(O₂)-(optionallysubstituted alkyl), —S(O₂)-optionally substituted aryl),—S(O₂)-(optionally substituted heterocyclyl), —S(O₂)-(optionallysubstituted alkoxy), —S(O₂)-optionally substituted aryloxy), and—S(O₂)-(optionally substituted heterocyclyloxy).

Preparation of Compounds

The compounds of the invention can be prepared by one skilled in the artbased only on knowledge of the compound's chemical structure. Thechemistry for the preparation of the compounds of this invention isknown to those skilled in the art. In fact, there is more than oneprocess to prepare the compounds of the invention. Specific examples ofmethods of preparation can be found in the art. For examples, see M.Barvian et al. J. Med. Chem. 2000, 43, 4606-4616; S. N. VanderWei et al.J. Med. Chem. 2005, 48, 2371-2387; P. L. Toogood et al. J. Med. Chem.2005, 48, 2388-2406; J. Kasparec et al. Tetrahedron Letters 2003, 44,4567-4570; and references cited therein. See also U.S. Pre-grantpublication US2004/0009993 A1 (M. Angiolini et al.), which isincorporated herein by reference, and references cited therein.

The following examples illustrate but do not limit the invention. Allreferences cited herein are incorporated by reference in their entirety.

Examples

Using the same or analogous schemes described above and/or substitutingwith alternative reagents, the following compounds of the invention wereprepared.

Illustrative compounds of Section II are shown in Table 1.

TABLE 1 Section II Example Structure Name 1

6-bromo-8-ethyl-4-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one 2

6-bromo-8-ethyl-4-methyl-2- [(phenylmethyl)amino]pyrido[2,3-d]pyrimidin-7(8H)-one 3

6-bromo-8-ethyl-4-methyl-2-(phenylamino)pyrido[2,3-d]pyrimidin-7(8H)-one 4

8-ethyl-2-(ethylamino)-4-methyl-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one 5

6-bromo-8-ethyl-4-methyl-2-[(1-methylethyl)amino]pyrido[2,3-d]pyrimidin-7(8H)- one 6

6-bromo-2-[(1,1-dimethylethyl)amino]-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one 7

6-bromo-2-(cyclopentylamino)-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one 8

8-ethyl-4-methyl-6-phenyl-2-(phenylamino)pyrido[2,3-d]pyrimidin-7(8H)-one 9

6-biphenyl-4-yl-8-ethyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one 10

6-(2,4-difluorophenyl)-8-ethyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one 11

6-(3-chloro-4-fluorophenyl)-8-ethyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one 12

8-ethyl-2-(ethylamino)-4-methyl-6-[4-(methyloxy)phenyl]pyrido[2,3-d]pyrimidin-7(8H)- one 13

6-(2,4-dichlorophenyl)-8-ethyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one 14

6-(3,4-difluorophenyl)-8-ethyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one 15

8-ethyl-2-(ethylamino)-4-methyl-6-[2-(methyloxy)phenyl]pyrido[2,3-d]pyrimidin-7(8H)- one 16

6-bromo-2-(cyclohexylamino)-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one 17

6-bromo-8-ethyl-4-methyl-2-[(2-morpholin-4-ylethyl)amino]pyrido[2,3-d]pyrimidin-7(8H)-one 18

6-bromo-8-ethyl-4-methyl-2-[(3-morpholin-4-ylpropyl)amino]pyrido[2,3-d]pyrimidin-7(8H)-one 19

6-bromo-2-{[3-(dimethylamino)propyl]amino}-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one 20

8-ethyl-2-(ethylamino)-4-methyl-6-[4-(phenyloxy)phenyl]pyrido[2,3-d]pyrimidin-7(8H)- one 21

6-[2,4-bis(methyloxy)phenyl]-8-ethyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin- 7(8H)-one 22

6-bromo-8-ethyl-2-[(2-fluorophenyl)amino]-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one 23

8-ethyl-2-(ethylamino)-6-(3-fluorophenyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one 24

8-ethyl-2-(ethylamino)-6-(2-fluorophenyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one 25

8-ethyl-2-(ethylamino)-4-methyl-6-[3-(trifluoromethyl)phenyl]pyrido[2,3-d]pyrimidin- 7(8H)-one 26

8-ethyl-2-(ethylamino)-6-(4-fluorophenyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one 27

8-ethyl-2-(ethylamino)-4-methyl-6-(2-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one 28

8-ethyl-2-(ethylamino)-4-methyl-6-[3-(methyloxy)phenyl]pyrido[2,3-d]pyrimidin-7(8H)- one 29

6-(3-chlorophenyl)-8-ethyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one 30

6-bromo-8-ethyl-4-methyl-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrido[2,3-d]pyrimidin-7(8H)- one 31

6-(4-chlorophenyl)-8-ethyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one 32

8-ethyl-2-(ethylamino)-4-methyl-6-(3-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one 33

8-ethyl-2-(ethylamino)-4-methyl-6-(4-methyl-2-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one 34

8-ethyl-2-(ethylamino)-4-methyl-6-(4-methyl-3-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one 35

1,1-dimethylethyl 2-[8-ethyl-2-(ethylamino)-4-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl]-1H-pyrrole-1-carboxylate 36

6-bromo-8-ethyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methylpyrido[2,3-d]pyrimidin- 7(8H)-one 37

6-bromo-8-ethyl-4-methyl-2-[(4-morpholin-4-ylphenyl)amino[pyrido[2,3-d]pyrimidin-7(8H)-one 38

6-bromo-8-ethyl-4-methyl-2-({4-[4- (phenylmethyl)piperazin-1-yl]phenyl}amino)pyrido[2,3-d]pyrimidin-7(8H)-one 39

8-ethyl-2-(ethylamino)-4-methyl-6-(1H-pyrrol-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one 40

6-(5-chloro-2-thienyl)-8-ethyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one 41

8-ethyl-4-methyl-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(2-thienyl)pyrido[2,3- d]pyrimidin-7(8H)-one 42

8-ethyl-2-(ethylamino)-4-methyl-6-pyrimidin-5-ylpyrido[2,3-d]pyrimidin-7(8H)-one 43

8-ethyl-2-(ethylamino)-6-(3-fluoropyridin-4-yl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one 44

8-ethyl-2-(ethylamino)-6-furan-3-yl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one 45

8-ethyl-2-(ethylamino)-4-methyl-6-[1-(phenylmethyl)-1H-pyrazol-4-yl]pyrido[2,3- d]pyrimidin-7(8H)-one 46

6-(3,5-dimethylisoxazol-4-yl)-8-ethyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin- 7(8H)-one 47

8-ethyl-4-methyl-2-({4-[4-(phenylmethyl)piperazin-1-yl]phenyl}amino)-6-(2-thienyl)pyrido[2,3- d]pyrimidin-7(8H)-one 48

6-bromo-2-(ethylamino)-4-methyl-8-(1-methylethyl)pyrido[2,3-d]pyrimidin-7(8H)-one 49

2-(ethylamino)-4-methyl-8-(1-methylethyl)-6-(2-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one 50

8-ethyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-6-(2-thienyl)pyrido[2,3-d]pyrimidin- 7(8H)-one 51

8-ethyl-2-(ethylamino)-6-(1H-indol-6-yl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one 52

8-ethyl-2-(ethylamino)-4-methyl-6-(5-phenyl-2-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one 53

2-(ethylamino)-6-furan-3-yl-4-methyl-8-(1-methylethyl)pyrido[2,3-d]pyrimidin-7(8H)-one 54

6-bromo-8-ethyl-2-(ethylamino)-4- methylpyrido[2,3-d]pyrimidin-7(8H)-one55

8-ethyl-2-(ethylamino)-4-methylpyrido[2,3- d]pyrimidin-7(8H)-one 56

8-ethyl-2-(ethylamino)pyrido[2,3-d]pyrimidin- 7(8H)-one 57

8-ethyl-2-(ethylamino)-4-methyl-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one 58

6-bromo-8-ethyl-2-(ethylamino)pyrido[2,3- d]pyrimidin-7(8H)-one 59

8-ethyl-2-(ethylamino)-4-methyl-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one 60

8-ethyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-6-furan-3-yl-4-methylpyrido[2,3-d]pyrimidin-7(8H)- one 61

8-ethyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one 62

2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-8-(1-methylethyl)-6-(2-thienyl)pyrido[2,3- d]pyrimidin-7(8H)-one63

8-ethyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-6-(3-fluorophenyl)-4-methylpyrido[2,3-d]pyrimidin- 7(8H)-one 64

2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-8-(1-methylethyl)-6-phenylpyrido[2,3- d]pyrimidin-7(8H)-one 65

2-[(4-{[2-(diethylamino)ethyl]oxy}phenyl)amino]-8-ethyl-4-methyl-6-phenylpyrido[2,3-d]pyrimidin- 7(8H)-one 66

8-ethyl-2-[(4-hydroxyphenyl)amino]-4-methyl-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one 67

8-cyclohexyl-2-(ethylamino)-4-methyl-6-(2-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one 68

8-ethyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-6-(1H-pyrazol-5-yl)pyrido[2,3- d]pyrimidin-7(8H)-one 69

6-(3,5-difluorophenyl)-8-ethyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one 70

8-ethyl-4-methyl-6-phenyl-2-({4-[(2-piperidin-1-ylethyl)oxy]phenyl}amino)pyrido[2,3-d]pyrimidin- 7(8H)-one 71

8-ethyl-4-methyl-2-({4-[(2-morpholin-4-ylethyl)oxy]phenyl}amino)-6-phenylpyrido[2,3- d]pyrimidin-7(8H)-one 72

6-bromo-2-(ethylamino)-4-methyl-8-[3-(methyloxy)propyl]pyrido[2,3-d]pyrimidin-7(8H)- one 73

6-bromo-2-(ethylamino)-8-[2-(ethyloxy)ethyl]-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one 74

6-bromo-2-(ethylamino)-4-methyl-8-(2-piperidin-1-ylethyl)pyrido[2,3-d]pyrimidin-7(8H)-one 75

6-bromo-2-(ethylamino)-8-[3-(ethyloxy)propyl]-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one 76

6-bromo-2-(ethylamino)-4-methyl-8-{3-[(1-methylethyl)oxy]propyl}pyrido[2,3-d]pyrimidin- 7(8H)-one 77

6-bromo-2-(ethylamino)-8-(3-hydroxypropyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one 78

6-bromo-2-(ethylamino)-8-(2-hydroxyethyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one 79

6-bromo-8-cyclopropyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one 80

6-bromo-2-{[4-(4-ethylpiperazin-1- yl)phenyl]amino}-4-methyl-8-(1-methylethyl)pyrido[2,3-d]pyrimidin-7(8H)-one 81

2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-8-(1-methylethyl)-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one 82

6-acetyl-8-ethyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methylpyrido[2,3-d]pyrimidin- 7(8H)-one 83

8-ethyl-2-(ethylamino)-4-methyl-6-(1,3-thiazol-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one 84

6-bromo-8-cyclopentyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one 85

8-cyclopentyl-2-(ethylamino)-4-methyl-6-(1H-pyrazol-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one 86

cyclopentyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one 87

2-(ethylamino)-4-methyl-8-(1-methylethyl)-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one 88

8-ethyl-2-(ethylamino)-4-methyl-6-(1H-pyrazol-1-yl)pyrido[2,3-d]pyrimidin-7(8H)-one 89

2-(ethylamino)-4-methyl-8-(1-methylethyl)-6-(1H-pyrazol-1-yl)pyrido[2,3-d]pyrimidin-7(8H)-one 90

8-cyclopentyl-2-(ethylamino)-4-methyl-6-(1H-pyrazol-1-yl)pyrido[2,3-d]pyrimidin-7(8H)-one 91

8-ethyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-6-(1H-pyrazol-1-yl)pyrido[2,3- d]pyrimidin-7(8H)-one 92

2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-8-(1-methylethyl)-6-(1H-pyrazol-1-yl)pyrido[2,3-d]pyrimidin-7(8H)-one 93

8-cyclopentyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-6-(1H-pyrazol-1-yl)pyrido[2,3-d]pyrimidin-7(8H)-one

In one embodiment of the invention, the PI3K inhibitor is selected fromthe compounds in Table I having a PI3K-binding affinity of about 9 μM orless. In another embodiment, the PI3K inhibitor is selected from thecompounds in Table I having a PI3K-binding affinity of about 5 μM orless. In another embodiment, the PI3K inhibitor is selected from thecompounds in Table I having a PI3K-binding affinity of about 3 μM orless. In another embodiment, the PI3K inhibitor is selected from thecompounds in Table I having a PI3K-binding affinity of about 1.5 μM orless. In another embodiment, the PI3K inhibitor is selected from thecompounds in Table I having a PI3K-binding affinity of about 1 μM orless. In another embodiment, the PI3K inhibitor is selected from thecompounds in Table I having a PI3K-binding affinity of about 0.6 μM orless. In another embodiment, the PI3K inhibitor is selected from thecompounds in Table I having a PI3K-binding affinity of about 0.3 μM orless. In another embodiment, the PI3K inhibitor is selected from thecompounds in Table I having a PI3K-binding affinity of about 0.2 μM orless. In another embodiment, the PI3K inhibitor is selected from thecompounds in Table I having a PI3K-binding affinity of about 0.1 μM orless. In another embodiment, the PI3K inhibitor is selected from thecompounds in Table I having a PI3K-binding affinity of about 0.04 μM orless. In another embodiment, the PI3K inhibitor is selected from thecompounds in Table I having a PI3K-binding affinity of about 0.020 μM orless.

In Vitro Enzymatic Assay Description for Sections II and III: PI3KalphaLuciferase-Coupled Chemiluminescence Assay Protocol

PI3Kalpha activity is measured as the percent of ATP consumed followingthe kinase reaction using luciferase-luciferin-coupledchemiluminescence. Reactions were conducted in 384-well white, mediumbinding microtiter plates (Greiner). Kinase reactions were initiated bycombining test compounds, ATP, substrate (PIP2), and kinase in a 20 μLvolume. The standard assay concentrations for enzyme, ATP, and substrateare 1.1 nm, 1 μM, and 7.5 μM, respectively. The reaction mixture wasincubated at ambient temperature for 2 h. Following the kinase reaction,a 10 μL aliquot of luciferase-luciferin mix (Promega Kinase-Glo) wasadded and the chemiluminescence signal measured using a Victor2 platereader (Perkin Elmer). Total ATP consumption was limited to 40-60% andIC50 values of control compounds correlate well with literaturereferences. In this assay, preferred compounds of the invention exhibitan IC₅₀ of less than 50 micromolar. More preferred compounds of theinvention exhibit an IC₅₀ of less than I micromolar. Even more preferredcompounds of the invention exhibit an IC₅₀ of less than 500 nanomolar.Still more preferred compounds of the invention exhibit an IC50 of lessthan 250 nanomolar.

Cell Assay Descriptions: Phospho AKT Assay

PC3 cells were seeded on 6-well plates at 150,000 cells/well. Cells werecultured for 3 days, then treated with compounds in serum-free mediumfor 3 hr. EGF (100 ng/ml) was added for the last 10 min. Cells werelysed in TENN buffer. Phospho T308 Akt and total Akt were quantified byELISA performed according to the Biosource assay protocol. The readingsof phospho Akt were normalized to total Akt readings.

Phospho S6 Assay

PC3 cells were seeded on 96-well plates at 8,000 cells/well. For eachexperiment, cells were seeded and treated in duplicated plates: oneplate for phospho S6 CellELISA, and one plate for total S6 CellELISA.Cells were cultured on the plates for 3 days, then treated withcompounds in serum-free medium for 3 hr in triplicate. Cells were fixedwith 4% formaldehyde, quenched with 0.6% H₂O₂, blocked with 5% BSA,incubated with either phospho S6 antibody or total S6 antibodyovernight, incubated with goat-anti-rabbit-IgG-HRP for 1 hr, anddeveloped in chemiluminescent substrate.

PIP3 Assay

MCF-7 cells grown in 10-cm dishes were starved for 3 hours in DMEM, andthen treated with compounds for 20 minutes. In the last 2 minutes of theincubation with the compounds, EGF (100 ng/ml) was added to stimulatethe production of PIP3. The medium was aspirated and the cells werescraped with 10% trichloroacetic acid. The lipids were extracted fromthe pellet after the cell lysates were centrifuged. PIP3 in the cellularlipid extraction was quantified with the AlpbaScreen assay in whichGrp1-PH is used as the PIP3 specific probe. The amount of cellular PIP3was calculated from the standard curve of diC₈ PI (3,4,5) P3.

Section III

In one embodiment, in section III the invention provides a compound ofFormula VIII:

or a pharmaceutically acceptable salt or solvate thereof, wherein

-   W¹, W², W³, and W⁴ are —C(R₁)— or one or two of W¹, W², W³, and W⁴    are independently —N— and the remaining are —C(R₁)—;-   X is —N(R₅)—;-   A is aryl, arylalkyl, —S(O)₂-aryl, heteroaryl, cycloalkyl,    heterocycloalkyl, halo, haloalkyl, haloalkoxy, C₁-C₆-alkyl,    C₁-C₆-alkoxy, or —C₁-C₆-alkyl-N(R₇)R_(7a), where each of the aryl,    heteroaryl, cycloalkyl, heterocycloalkyl, and alkyl groups, each    either alone or as part of another group within A, is independently    optionally substituted with (R₂)_(n1);-   B is aryl, heteroaryl, C₁-C₆-alkyl, —C₁-C₆-alkylaryl, or    —C₁-C₆-alkylheteroaryl, wherein each of the aryl, heteroaryl and    alkyl groups are independently optionally substituted with    (R₃)_(n2);-   n1 and n2 are independently 0 or an integer from 1 to 5;-   each R₁ is independently hydrogen, C₁-C₆-alkyl, haloalkyl,    C₁-C₆-alkoxy, haloalkoxy, —NO₂, halo, hydroxy, hydroxyalkyl, —CN,    cyanoalkyl, or —C₀-C₆ alkyl-N(R₁₀)R_(10a) where R₁₀ and R_(10a) are    independently hydrogen, —C₁-C₆-alkyl, —OH, —O—C₁-C₆ alkyl,    haloalkyl, or haloalkoxy;-   each R₂ (when R₂ is present) is independently selected from    —C₁-C₆-alkanyl, —C₁-C₆-alkenyl, —C₂-C₆-alkenyl-C(O)OR₆, —OR₆,    —N(R₇)C(O)R₆, —N(R₇)C(O)—C₀-C₆-alkyl —N(R_(7b))R_(7a),    —OC(O)—C₀-C₆-alkyl-N(R₇)R_(7a), —N(R₇)C(O)—C₁-C₆-alkylC(O)OR₆,    —C₀-C₆-alkyl-C(O)R₆, —S(O)₂N(R₇)R_(7a), —C(O)OR₆, —CH(R₆)₂—C(O)OR₆,    —S(O)₂R₆, cycloalkyl, heterocycloalkyl, heteroaryl,    —C(O)N(R₇)—C₁-C₆-alkyl-OR₆,    —C₀-C₆-alkyl-C(O)N(R₇)—C₁-C₆-alkyl-C(O)OR₆,    —C₀-C₆-alkyl-C(O)N(R₇)R_(7a), aryl, arylalkyl, —S—(C₁-C₆-alkyl),    halo, oxo, —NO₂, —S—CN, —CN, and —C₀-C₆-alkyl-N(R₇)R_(7a), wherein    each of the alkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, and    heteroaryl groups, either alone or as part of another group within    R₂, is independently optionally substituted with 1, 2, 3, 4, or 5    groups selected from C₁-C₆-alkyl, halo, haloalkyl, haloalkoxy, oxo,    —NO₂, —CN, —OH, —N(R₈)R_(8a), C₁-C₆-alkoxy, and —C(O)OR₉;-   each R₃ (when R₃ is present) is independently NO₂, halo, —CN,    C₁-C₆-alkanyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₁-C₆-alkoxy,    C₃-C₆-cycloalkyl, C₀-C₆-alkyl-heterocycloalkyl,    —C₀-C₆-alkyl-N(R₇)C(O)—C₀-C₆-alkyl-N(R_(7b))R_(7a),    —C₀-C₆-alkyl-N(R₇)C(O)—C₀-C₆-alkyl-N(R_(7b))C(O)R_(7a), —C₀-C₆    alkyl-C(O)—C₀-C₆-alkyl-N(R₇)R_(7a),    —C₀-C₆-alkyl-C(O)N(R₇)—C₀-C₆-alkyl-N(R_(7b))R_(7a),    —C₀-C₆-alkyl-C(O)N(R₇)—C₁-C₆alkylC(O)OR_(7a),    —C₀-C₆-alkyl-N(R₇)C(O)—C₀-C₆-alkyl-(R_(7a)),    —C₀-C₆-alkyl-N(R₇)—C₀-C₆-alkyl-N(R_(7b))R_(7a),    —C₀-C₆-alkyl-N(R₇)C(O)—C₀-C₆-alkyl-N(R_(7b))—C₀-C₆-alkyl-N(R_(7c))(R_(7a)),    —C₀-C₆-alkyl-N(R₇)C(O)O—C₀-C₆-alkyl-N(R_(7b))R_(7a),    —C₀-C₆-alkyl-N(R₇)C(O)O—C₀-C₆-alkyl-aryl,    —C₀-C₆-alkyl-C(O)N(R₇)—C₀-C₆-alkyl-N(R_(7b))R_(7a),    —C₀-C₆-alkyl-N(R₇)—C₀-C₆-alkyl-C(═N(R_(7b))(R_(7a)))(NR_(7c)R_(7d)),    —C₀-C₆-alkyl-aryl, —C₀-C₆-alkyl-heteroaryl,    —C₀-C₆-alkyl-heterocycloalkyl, —O—C₁-C₆-alkyl-N(R₇)R_(7a),    —C₀-C₆-alkyl-OR₆, —C₀-C₆ alkyl-C(O)OR₆, —C₀-C₆-alkyl-N(R₇)R_(7a),    —C₀-C₆-alkyl-C(O)NR₇R_(7a), —C₀-C₆-alkyl-C(O)-R₇, —SR₇, —S(O)₂R₇,    —S(O)₃R₇, —S(O)R₇, —S(O)₂N(R₇)—C₀-C₆-alkyl-N(R_(7b))R_(7a),    —S-heteroaryl, —S-aryl, —S-heterocycloalkyl,    —C₀-C₆-alkyl-N(R₇)-aryl, —C₀-C₆-alkyl-N(R₇)-heteroaryl,    —C₀-C₆-alkyl-N(R₇)-heterocycloalkyl,    —C₀-C₆-alkyl-C(O)N(R₇)—C₀-C₆-alkyl-cycloalkyl,    —C₀-C₆-alkyl-C(O)N(R₇)—C₀-C₆-alkyl-aryl,    —C₀-C₆-alkyl-C(O)N(R₇)—C₀-C₆-alkyl-heteroaryl,    —C₀-C₆-alkyl-C(O)N(R₇)—C₀-C₆-alkyl-heterocycloalkyl,    —C₀-C₆-alkyl-N(R₇)C(O)—C₀-C₆-alkyl-cycloalkyl,    —C₀-C₆-alkyl-N(R₇)C(O)—C₀-C₆-alkyl-aryl,    —C₀-C₆-alkyl-N(R₇)C(O)-C₀-C₆-alkyl-heteroaryl,    —C₀-C6-alkyl-N(R₇)C(O)—C₀-C6-alkyl-heterocycloalkyl,    —C₀-C₆-alkyl-N(R₇)C(O)—C₀-C₆-alkyl-heterocycloalkyl-aryl,    —N(R₇)C(O)OR₆, or —N(R₇)—C(O)—R_(7a), wherein each of the alkyl,    alkanyl, alkenyl, cycloalkyl, aryl, alkoxy, heterocycloalkyl, and    heteroaryl groups, either alone or as part of another group within    R₃, is independently optionally substituted with 1, 2, 3, 4, or 5    groups selected from C₁-C₆-alkanyl, C₁-C₆-alkenyl, —C₀-C₆-alkyl-OR₉,    cycloalkyl, halo, haloalkyl, haloalkoxy, —C(O)R₉, —NO₂, —CN, oxo,    —C₀-C₆-alkyl-N(R₈)R_(8a), —C₀-C₆-alkyl-heterocycloalkyl,    —C₀-C₆-alkyl-aryl, —C₀-C₆-alkyl-heteroaryl, —C(O)OR₉, and    hydroxyalkyl;-   R₄ is hydrogen, aryl, —C₀-C₆-alkyl-N(R₇)R_(7a), C₁-C₆-alkoxy, or    C₁-C₆ alkyl, wherein each of the alkyl and aryl groups, either alone    or as part of another group in R₄, is independently optionally    substituted with 1, 2, 3, 4, or 5 groups selected from C₁-C₆-alkyl,    halo, haloalkyl, haloalkoxy, —NO₂, —CN, —OH, —N(R₈)R_(8a),    C₁-C₆-alkoxy, and —C(O)OR₆;-   R₅ is hydrogen, —C₁-C₆-alkyl-N(R₇)R_(7a), C₁-C₆-alkoxy, C₁-C₆-alkyl,    or aryl, wherein each of the alkyl and aryl is optionally    substituted with 1, 2, 3, 4, or 5 groups selected from C₁-C₆-alkyl,    halo, haloalkyl, haloalkoxy, —NO₂, —CN, —OH, —N(R₈)R_(8a),    C₁-C₆-alkoxy, or —C(O)OR₆; or-   R₆ and R₉ are independently hydrogen, —OH, C₁-C₆-alkyl, aryl,    arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,    heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, or aryl, each    C₁-C₆ alkyl, aryl, cycloalkyl, heterocycloalkyl, and heteroaryl,    either alone or as part of another group within R₆ and R₉, is    independently optionally substituted with 1, 2, 3, 4, or 5 groups    independently selected from —NH₂, —OH, C₁-C₆-alkoxy, C₁-C₆-alkyl,    and halo; and-   R₇, R_(7a), R_(7b), R_(7c), R_(7d), R₈, and R_(8a) are independently    hydrogen, —C₁-C₆-alkanyl, —OH, —O—C₁-C₆ alkanyl, —O—C₁-C₆ alkenyl,    —O—C₀-C₆-alkyl-aryl, —C₀-C₆-alkyl-C(O)OR₆, —C₀-C₆-alkyl-C(O)R₆,    aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl,    cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl, wherein    each of the alkyl, aryl, heteroaryl, and heterocycloalkyl, either    alone or part of another group within R₇, R_(7a), R_(7b), R_(7c),    and R_(7d), is independently optionally substituted with 1, 2, 3, 4,    or 5 groups selected from —NH₂, alkylamino, dialkylamino,    —S—C₁-C₆-alkyl, —CN, —OH, —NO₂, oxo, C₁-C₆-alkoxy, C₁-C₆-alkyl,    halo, aryl, and heteroaryl optionally substituted with one or two    C₁-C₆-alkyl.

In one embodiment, in section III the invention provides a compound ofFormula VIIIa:

or a pharmaceutically acceptable salt or solvate thereof, wherein

-   W¹, W², W³, and W⁴ are —C(R₁)— or W² and W³ are —C(R₁)— and one of    W¹ and W⁴ is —N— and the other is —C(R₁)—;-   X is —N(R₅)—;-   A is aryl, heteroaryl, or heterocycloalkyl where the aryl,    heteroaryl, and heterocycloalkyl are optionally substituted with    (R₂)_(n1); or-   B is aryl, —C₁-C₆ alkylaryl, heteroaryl, or heterocycloalkyl, where    the aryl, C₁-C₆-alkyl, heteroaryl, and heterocycloalkyl are    independently optionally substituted with (R₃)_(n2);-   n1 is 0, 1, 2, or 3;-   n2 is or an integer from 1 to 5;-   each R₁ is independently hydrogen, C₁-C₆-alkyl, haloalkyl,    C₁-C₆-alkoxy, haloalkoxy, or —NO₂;-   each R₂ (when R₂ is present) is independently —C₁-C₆-alkanyl,    —C₁-C₆-alkenyl, —OR₆, —N(R₇)—C(O)—R₆, —N(R₇)—C(O)—C₀-C₆    alkyl-N(R_(7b))R_(7a), —OC(O)—C₀-C₆ alkyl-N(R₇)R_(7a),    —C₀-C₆alkyl-C(O)R₆, heterocycloalkyl, aryl, halo, —NO₂, or    —C₀-C₆-alkyl-N(R₇)R_(7a), wherein each alkyl, aryl, and    heterocycloalkyl groups, each either alone or as part of another    group within R₂, is independently optionally substituted with one,    two, three, four, or five groups selected from C₁-C₆-alkyl,    C₁-C₆-alkoxy, halo, haloalkyl, and haloalkoxy;-   each R₃ (when R₃ is present) is independently hydroxy, —NO₂, halo,    —CN, C₁-C₆-alkanyl, C₂-C₆-alkenyl, C₁-C₆ alkoxy, —C₀-C₆    alkyl-N(R₇)C(O)—C₀-C₆-alkyl-N(R_(7b))R_(7a),    —C₀-C₆-alkyl-N(R₇)C(O)—C₀-C₆-alkyl-N(R_(7b))C(O)R_(7a), —C₀-C₆    alkyl-C(O)N(R₇)—C₀-C₆-alkyl-N(R₇)R_(7a),    —C₀-C₆-alkyl-C(O)N(R₇)—C₁-C₆-alkyl-C(O)OR_(7a),    —C₀-C₆-alkyl-N(R₇)—C(O)—C₀-C₆-alkyl-(R₇),    —C₀-C₆-alkyl-N(R₇)—C₀-C₆-alkyl-N(R₇)R_(7a),    —C₀-C₆-alkyl-N(R₇)C(O)—C₀-C₆-alkyl-N(R_(7b))—C₀-C₆-alkyl-N(R_(7c))R_(7a),    —C₀-C₆-alkyl-N(R₇)C(O)O—C₀-C₆-alkyl-N(R_(7b))R_(7a),    —C₀-C₆-alkyl-N(R₇)—C₀-C₆ alkyl-C(═N(R_(7b))(R_(7a)))(NR_(7c)R_(7d)),    —C₀-C₆-alkyl-heteroaryl, —C₀-C₆-alkyl-OR₆, —C₀-C₆-alkyl-C(O)OR₆,    —C₀-C₆-alkyl-N(R₇)R_(7a), —C₀-C₆-alkyl-C(O)—NR₇R_(7a),    —C₀-C₆-alkyl-C(O)—R₇, —S(O)₂R₇, —SO₂N(R₇)—C₀-C₆-alkyl-N(R₇)R_(7a),    —C₀-C₆-alkyl-C(O)-heterocycloalkyl (dupe of C(O)R7),    —C₀-C₆-alkyl-C(O)N(R₇)—C₀-C₆-alkyl-heterocycloalkyl,    —C₀-C₆-alkyl-N(R₇)C(O)—C₀-C₆-alkyl-cycloalkyl,    —C₀-C₆-alkyl-N(R₇)—C(O)—C₀-C₆-alkyl-aryl,    —C₀-C₆-alkyl-N(R₇)-C(O)—C₀-C₆-alkyl-heteroaryl,    —C₀-C₆-alkyl-N(R₇)C(O)—C₀-C₆-alkyl-heterocycloalkyl,    —C₀-C₆-alkyl-N(R₇)C(O)—C₀-C₆-alkyl-heterocycloalkyl-aryl, or    —N(R₇)C(O)R_(7a), wherein each of the alkyl, alkanyl, alkenyl,    cycloalkyl, aryl, alkoxy, heterocycloalkyl, and heteroaryl groups,    either alone or as part of another group within R₃, is independently    optionally substituted with 1, 2, 3, 4, or 5 groups selected from    C_(l)-C₆-alkanyl, C₁-C₆ alkenyl, cycloalkyl, halo, —C(O)—R₆, oxo,    hydroxy, —C₀-C₆-alkyl —N(R₈)R_(8a), —C₀-C₆-alkyl -heterocycloalkyl,    —C₀-C₆-alkyl-aryl, —C₀-C₆-alkyl-heteroaryl, —C(O)OR₆, and    hydroxyalkyl;-   R₄ is hydrogen;-   R₅ is hydrogen;-   R₆ and R₉ are independently hydrogen, C₁-C₆-alkyl, aryl, arylalkyl,    or cycloalkyl, where each of the —C₁-C₆-alkyl, aryl, arylalkyl, and    cycloalkyl, is independently optionally substituted with 1, 2, 3, 4,    or 5 groups selected from C₁-C6-alkoxy, C₁-C₆-alkyl, and halo; and-   R₇, R_(7a), R_(7b), R_(7c), and R_(7d) are independently hydrogen,    —C₁-C₆-alkanyl, —C₁-C₆-alkenyl, —OH, —O—C₁-C₆ alkanyl, —O—C₁-C₆    alkenyl, —O—C₀-C₆-alkyl-aryl, aryl, arylalkyl, heteroaryl,    heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or    heterocycloalkylalkyl, wherein each of the alkyl, aryl, heteroaryl,    and heterocycloalkyl, either alone or part of another group within    R₇, R_(7a), R_(7b), R_(7c), and R_(7d), is independently optionally    substituted with 1, 2, 3, 4, or 5 —NH₂, alkylamino, dialkylamino,    —S—C₁-C₆-alkyl, —CN, hydroxy, oxo, C₁-C₆ alkoxy, C₁-C₆ alkyl, or    halo.

In another embodiment (A1), the invention provides a compound of FormulaVIIIa where X is —N(R₅)—, R₅ is hydrogen, and all other groups are asdefined above for a compound of Formula VIIIa.

In another embodiment (A2), the invention provides a compound of FormulaVIIIa where A is aryl or heteroaryl where the aryl and the heteroarylare optionally substituted with (R₂)_(n1) where n1 is 1, 2, 3, 4, or 5;B is aryl or heteroaryl where the aryl and the heteroaryl are optionallysubstituted with (R₃)_(n2) where n2 is 1, 2, 3, 4, or 5; and all othergroups are as defined above for a compound of Formula VIIIa.

In another embodiment (A3), the invention provides a compound of FormulaVIIIa where W¹, W², W³, and W⁴ are —C(R₁)‘ where each R₁ isindependently hydrogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, or nitro; and allother groups are as defined in the Summary of the Invention. In anotherembodiment, W¹ and W⁴ are —CH— and W² and W³ are —C(R₁)— where each R₁is independently hydrogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, or nitro. Inanother embodiment, W¹ and W⁴ are —CH— and W² and W³ are —C(R₁)— whereeach R₁ is independently hydrogen, methyl, methoxy, or nitro. In anotherembodiment, W¹, W², W³, and W⁴ are —CH—.

In another embodiment, the invention provides a compound of FormulaVIIIb:

or a pharmaceutically acceptable salt or solvate thereof, wherein

-   n1 is one or two; and n2 is one or two; n3 is 0, 1, or two;-   each R₁ is independently hydrogen, C₁-C₆-alkyl, haloalkyl,    C₁-C₆-alkoxy, haloalkoxy, —NO₂, halo, hydroxy, hydroxyalkyl, —CN,    cyanoalkyl, or —C₀-C₆ alkyl-N(R₁₀)R_(10a) where R₁₀ and R_(10a) are    independently hydrogen, —C₁-C₆-alkyl, —OH, —O—C₁C₆ alkyl, haloalkyl,    or haloalkoxy;-   each R₂ (when R₂ is present) is independently C₁-C₆-alkanyl,    C₁-C₆-alkenyl, —OR₆, —N(R₇)—C(O)—R₆, —N(R₇)—C(O)—C₀-C₆    alkyl-N(R_(7b))R_(7a), —OC(O)—C₀-C₆ alkyl-N(R₇)R_(7a),    —C₀-C₆alkyl-C(O)R₆, heterocycloalkyl, aryl, halo, —NO₂, or    —C₀-C₆-alkyl-N(R₇)R_(7a), wherein each alkyl, aryl, and    heterocycloalkyl groups, each either alone or as part of another    group within R₂, is independently optionally substituted with one,    two, three, four, or five groups selected from C₁-C₆-alkyl,    C₁-C₆-alkoxy, halo, haloalkyl, and haloalkoxy;-   each R₃ (when R₃ is present) is independently hydroxy, —NO₂, halo,    —CN, C₁-C₆-alkanyl, C₂-C₆-alkenyl, C₁-C₆ alkoxy, —C₀-C₆ alkyl    —N(R₇)C(O)—C₀-C₆-alkyl-N(R_(7b))R_(7a),    —C₀-C₆-alkyl-N(R₇)C(O)—C₀-C₆-alkyl-N(R_(7b))C(O)R_(7a), —C₀-C₆    alkyl-C(O)N(R₇)—C₀-C₆-alkyl-N(R₇)R_(7a),    —C₀-C₆-alkyl-C(O)N(R₇)—C₁-C₆-alkyl-C(O)OR_(7a),    —C₀-C₆-alkyl-N(R₇)—C(O)—C_(O)-C₆-alkyl-(R₇),    —C₀-C₆-alkyl-N(R₇)—C₀-C₆-alkyl-N(R₇)R_(7a),    —C₀-C₆-alkyl-N(R₇)C(O)—C₀-C₆-alkyl-N(R_(7b))—C₀-C₆-alkyl-N(R_(7c))R_(7a),    —C₀-C₆-alkyl-N(R₇)C(O)O—C₀-C₆-alkyl-N(R_(7b))R_(7a),    —C₀-C₆-alkyl-N(R₇)—C₀-C₆ alkyl-C(═N(R_(7b))(R_(7a)))(NR_(7c)R_(7d)),    —C₀-C₆-alkyl-heteroaryl, —C₀-C_(C) ₆-alkyl-OR₆,    —C₀-C₆-alkyl-C(O)OR₆, —C₀-C₆-alkyl-N(R₇)R_(7a),    —C₀-C₆-alkyl-C(O)—NR₇R_(7a), —C₀-C₆-alkyl-C(O)—R₇, —S(O)₂R₇,    —SO₂N(R₇)—C₀-C₆-alkyl-N(R₇)R_(7a),    —C₀-C₆-alkyl-C(O)-heterocycloalkyl (dupe of C(O)R7),    —C₀-C₆-alkyl-C(O)N(R₇)—C₀-C₆-alkyl-heterocycloalkyl,    —C₀-C₆-alkyl-N(R₇)C(O)—C₀-C₆-alkyl-cycloalkyl,    —C₀-C₆-alkyl-N(R₇)—C(O)—C₀-C₆-alkyl-aryl,    —C₀-C₆-alkyl-N(R₇)—C(O)—C₀-C₆-alkyl-heteroaryl,    —C₀-C₆-alkyl-N(R₇)C(O)—C₀-C₆-alkyl-heterocycloalkyl,    —C₀-C₆-alkyl-N(R₇)C(O)—C₀-C₆-alkyl-heterocycloalkyl-aryl, or    —N(R₇)C(O)R_(7a), wherein each of the alkyl, alkanyl, alkenyl,    cycloalkyl, aryl, alkoxy, heterocycloalkyl, and heteroaryl groups,    either alone or as part of another group within R₃, is independently    optionally substituted with 1, 2, 3, 4, or 5 groups selected from    C₁-C₆-alkanyl, C₁-C₆ alkenyl, cycloalkyl, halo, —C(O)—R₆, oxo,    hydroxy, —C₀-C₆-alkyl-N(R₈)R_(8a), —C₀-C₆-alkyl-heterocycloalkyl,    —C₀-C₆-alkyl-aryl, —C₀-C₆-alkyl-heteroaryl, —C(O)OR₆, and    hydroxyalkyl;-   R₄ is hydrogen;-   R₅ is hydrogen;-   R₆ is hydrogen, C₁-C₆-alkyl, aryl, arylalkyl, or cycloalkyl, where    each of the —C₁-C₆-alkyl, aryl, arylalkyl, and cycloalkyl, is    independently optionally substituted with 1, 2, 3, 4, or 5 groups    selected from C₁-C₆-alkoxy, C₁-C₆-alkyl, and halo; and-   R₇, R_(7a)R_(7b), R_(7c), and R_(7d) are independently hydrogen,    —C₁-C₆-alkanyl, —C₁-C₆-alkenyl, —OH, —O—C₁-C₆ alkanyl, —O—C₁-C₆    alkenyl, —O—C₀-C₆-alkyl-aryl, aryl, arylalkyl, heteroaryl,    heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or    heterocycloalkylalkyl, wherein each of the alkyl, aryl, heteroaryl,    and heterocycloalkyl, either alone or part of another group within    R₇, R_(7a), R_(7b), R_(7c), and R_(7d), is independently optionally    substituted with 1, 2, 3, 4, or 5 —NH₂, alkylamino, dialkylamino,    —S—C₁-C₆-alkyl, —CN, hydroxy, oxo, C₁-C₆ alkoxy, C₁-C₆ alkyl, or    halo.

In another embodiment (C), the invention provides a compound accordingto Embodiment B, wherein R₁ is hydrogen, —NO₂, C₁-C₄ alkoxy, or C₁-C₃alkyl. In another embodiment, one or two R₁ are hydrogen, methoxy, ormethyl and the remaining R₁ are hydrogen. In another embodiment, each R¹is hydrogen.

In another embodiment (D), the invention provides a compound accordingto Embodiment B wherein n1 is 1 or 2 and each R₂ is independently halo,—OR₆ (where R₆ is hydrogen or alkyl), —N(R₇)—C(O)—C₀-C₆alkyl-N(R_(7b))R_(7a) (where R₇, R_(7a), and R_(7b) are independentlyhydrogen or C₁-C₆-alkanyl), or —C₀-C₆alkyl-C(O)R₆ (where R₆ isC₁-C₆-alkanyl). In another embodiment, each R₂ is independently chloro,bromo, fluoro, hydroxy, methoxy, —N(H)C(O)—CH₂—N(CH₃)₂, —C(O)CH₃, ormethyl. In another embodiment, each R₂ is independently hydrogen,methoxy, or chloro.

In another embodiment (E), the invention provides a compound accordingto Embodiment B wherein n2 is 1 or 2 and each R₃ is independentlyC₁-C₆-alkanyl, C₁-C₆-alkenyl, halo,—C₀-C₆-alkyl-N(R₇)C(O)—C₀-C₆-alkyl-N(R_(7b))R_(7a),—C₀-C₆-alkyl-N(R₇)C(O)—C₀-C₆-alkyl-N(R_(7b))—C₀-C₆-alkyl-N(R_(7c))(R_(7a)),—C₀-C₆-alkyl-N(R₇)C(O)—C₀-C₆-alkyl-(R_(7a)),—C₀-C₆-alkyl-N(R₇)C(O)—C₀-C₆-alkyl-heterocycloalkyl,—C₀-C₆-alkyl-N(R₇)R_(7a), —C₀-C₆-alkyl-N(R₇)C(O)—C₀-C₆-alkyl-heteroaryl;where R₇, R_(7a), R_(7b), and R_(7c) are independently hydrogen,C₁-C₆-alkanyl, C₁-C₆-alkoxy, cycloalkylalkyl, hydroxy, orheterocycloalkyl (optionally substituted with C₁-C₆-alkyl); and wherethe alkyl and heterocycloalkyl, either alone or as part of another groupwithin R₃, are independently optionally substituted with 1, 2, or 3groups, preferably 1 or 2, selected from hydroxy, halo,—C₀-C₆-alkyl-N(R₈)R_(8a) (where R₈ and R_(8a) are independently hydrogenor C₁-C₆-alkanyl), and —C₀-C₆-alkyl-heteroaryl.

In another embodiment of embodiment E, n2 is 1 and R₃ is C₁-C₆-alkanyl,halo, —N(R₇)C(O)—C₁-C₆-alkyl-N(R_(7b))R_(7a),—N(R₇)C(O)—C₀-C₆-alkyl-N(R_(7b))—C₁-C₆-alkyl-N(R_(7c))(R_(7a)),—N(R₇)C(O)—C₀-C₆-alkyl-(R_(7a)),—N(R₇)C(O)—C₀-C₆-alkyl-heterocycloalkyl, —N(R₇)R_(7a), or—N(R₇)C(O)—C₁-C₆-alkyl-heteroaryl; where R₇, R_(7a), R_(7b), and R_(7c)are independently hydrogen, C₁-C₆-alkanyl, C₁-C₆-alkoxy,cycloalkylalkyl, hydroxy, or heterocycloalkyl (optionally substitutedwith C₁-C₆-alkyl); and where the alkyl either alone or as part ofanother group within R₃, is independently optionally substituted with 1,2, or 3 groups, preferably 1, or 2, groups selected from hydroxy, halo,—C₀-C₆-alkyl-N(R₈)R_(8a) (where R₈ and R_(8a) are independently hydrogenor C₁-C₆-alkanyl), and —C₁-C₆-alkyl-heteroaryl.

In another embodiment of embodiment E, n2 is 1 and R₃ is methyl, chloro,—NHC(O)CH₂NH(CH₃), —NHC(O)CH₂NH(CH₂CH₃), —NHC(O)CH(CH₃)NH₂,—NHC(O)C(CH₃)₂NH₂, —NHC(O)CH₂N(CH₃)₂, —NHC(O)CH₂N(CH₃)CH₂CH₂N(CH₃)₂,—NHC(O)CH(NH₂)CH₂CH₃, —NHC(O)CH₂N(CH₃)CH₂CH₂N(CH₃)₂,—NHC(O)CH(CH₃)NH(CH₃), —NHC(O)CH₂NH₂, —NHC(O)CH₂NH(CH₃),—NHC(O)CH₂N(CH₃)₂, —NHC(O)H, —NHC(O)CH₂(azetidin-1-yl),—NHC(O)(pyrrolidin-2-yl), —NHC(O)CH(NH₂)CH₂OH, —NHC(O)(azetidin-4-yl),—NHC(O)C(CH₃)₂NH(CH₃), —NH₂, —NHC(O)CH₂NH(CH₂CH₂CH₃), —NHC(O)CH₂CH₂NH₂,—NHOH, —NHC(O)(piperidin-3-yl), —NHC(O)(4-methyl-1,4-diazepan-1-yl),—NHC(O)CH(NH₂)(CH₂CH₃), —NHC(O)CH₂NH(CH₂CH(OH)(CH₃)),—NHC(O)CH₂NHCH₂CH₂F, —NHC(O)CH₂NH(OCH₂CH(CH₃)₂),—NHC(O)(1-aminocycloprop-1-yl), —NHC(O)CH₂NH(CH₂cyclopropyl),—NHC(O)CH₂(3-(dimethylamino)-azetidin-1-yl), —NHC(O)(piperidin-2-yl),—NHC(O)(morpholin-4-yl), —NHC(O)CH₂(pyrrolidin-1-yl),—NHC(O)CH(NH₂)CH₂CH₂CH₂CH₂N(CH₃)₂, —NHC(O)CH₂N(CH₃)(CH₂CH₃),—NHC(O)CH₂(imidazol-5-yl), —NHC(O)(1-aminocyclopent-1-yl),—NHC(O)CH₂NH(CH₂CH(CH₃)₂),—NHC(O)(N-(imidazol-4-ylmethyl)-azetidin-3-yl),—NHC(O)(N-ethyl-azetidin-3-yl), —NHCH₂N(CH₃)CH₂CH₂N(CH₃)₂,—NHC(O)CH₂N(CH₃)(N-methyl-pyrrolidin-3-yl), or—NHC(O)CH₂N(CH₃)(CH₂CH₂N(CH₃)₂).

In another embodiment of embodiment E, n2 is 1 and R₃ is methyl,—NHC(O)CH₂NH(CH₃), —NHC(O)CH(CH₃)NH₂, —NHC(O)C(CH₃)₂NH₂,—NHC(O)CH₂N(CH₃)₂, —NHC(O)CH₂N(CH₃)CH₂CH₂N(CH₃)₂, —NHC(O)CH(NH₂)CH₂CH₃,—NHC(O)CH₂N(CH₃)CH₂CH₂N(CH₃)₂, or —NHC(O)CH(CH₃)NH(CH₃).

In another embodiment (F), the invention provides a compound of FormulaVIIIb where n1 is two; R² is selected from —OR₆ (where R⁶ isC₁-C₆-alkyl) and halo; n2 is 1; R³ is —C₀-C₆alkyl-N(R₇)C(O)—C₀-C₆-alkyl-N(R_(7b))R_(7a) (where R₇, R_(7a), andR_(7b) are independently hydrogen or —C₁-C₆-alkanyl); and n3 is 0.

In one embodiment, in section III the invention provides a compound ofFormula IX:

or a pharmaceutically acceptable salt thereof, wherein

-   W¹, W², W³, and W⁴ are —C(R₁)— or one or two of W¹, W², W³, and W⁴    are independently —N— and the remaining are —C(R₁)—;-   X is a covalent bond, —N(R₅)—, —O—, —S—, or C₁-C₆ alkylene, wherein    the alkylene is optionally substituted with 1, 2, 3, 4, or 5 groups    selected from C₁-C₆ alkoxy, halo, haloalkoxy, —NO₂, —CN, —OH,    —N(R₇)R_(7a), and —C(O)—OR₆;-   A is aryl, —S(O)₂-aryl, heteroaryl, cycloalkyl, heterocycloalkyl,    halo, haloalkyl, haloalkoxy, C₁-C₆-alkyl, C₁-C₆-alkoxy, or    —C₁-C₆-alkyl-N(R₇)R_(7a), where each of the aryl, heteroaryl,    cycloalkyl, heterocycloalkyl, alkyl and alkoxy groups, each either    alone or as part of another group within A, are independently    optionally substituted with (R₂)_(n1);-   B is aryl, heteroaryl, C₁-C₆-alkyl, —C₁-C₆-alkylaryl, or    —C₁-C₆-alkylheteroaryl, wherein each of the aryl, heteroaryl and    alkyl groups are independently optionally substituted with    (R₃)_(n2);-   n1 and n2 are independently 0 or an integer from 1 to 5;-   each R₁ is independently selected from hydrogen, C₁-C₆-alkoxy,    C₁-C₆-alkyl, —NO₂, halo, —CN, and —C₀-C₆-alkyl-N(R₇)R_(7a), wherein    each of the alkyl and alkoxy groups is optionally substituted with    1, 2, 3, 4, or 5 groups selected from C₁-C₆-alkyl, C₁-C₆-alkoxy,    halo, haloalkyl, haloalkoxy, —NO₂, —CN, hydroxy, —N(R₈)R_(8a), and    —C(O)OR₆;-   each R₂ (when R₂ is present) is independently selected from    C₁-C₆-alkanyl, C₁-C₆-alkenyl, C₂-C₆-alkenyl-C(O)OR₆, —OR₆,    —N(R₇)C(O)R₆, —N(R₇)C(O)—C₀-C₆ alkyl-N(R_(7b))R_(7a), —OC(O)—C₀-C₆    alkyl-N(R₇)R_(7a), —N(R₇)C(O)—C₁-C₆ alkylC(O)OR₆,    C₀-C₆-alkyl-C(O)R₆, oxo, dioxo, —S(O)₂—N(R₇)R_(7a), —C(O)OR₆,    —CH(R₆)₂—C(O)—OR₆, —S(O)₂R₆, cycloalkyl, heterocycloalkyl,    heteroaryl, —C(O)N(R₇)—C₁-C₆-alkyl-OR₆, —C₀-C₆    alkyl-C(O)N(R₇)—C₀-C₆-alkyl-C(O)OR₆, —C₀-C₆-alkyl-C(O)N(R₇)R_(7a),    aryl, arylalkyl, —S—(C₁-C₆ alkyl), halo, oxo, —NO₂, —S—CN, —CN, and    —C₀-C₆ alkyl-N(R₇)R_(7a), wherein each of the alkyl (including, for    example the alkyl within alkoxy), aryl, cycloalkyl,    heterocycloalkyl, and heteroaryl groups, either alone or as part of    another group within R₂, is independently optionally substituted    with 1, 2, 3, 4, or 5 groups selected from C₁-C₆-alkyl, halo,    haloalkyl, haloalkoxy, oxo, —NO₂, —CN, —OH, —N(R₈)R_(8a),    C₁-C₆-alkoxy, and —C(O)OR₉;-   each R₃ (when R₃ is present) is independently oxo, —NO₂, halo, —CN,    C₁-C₆-alkanyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₁-C₆-alkoxy,    C₃-C₆-cycloalkyl, —C₀-C₆-alkyl-heterocycloalkyl, —C₀-C₆    alkyl-N(R₇)C(O)—C₀-C₆-alkyl-N(R_(7b))R_(7a), —C₀-C₆    alkyl-N(R₇)C(O)—C₀-C₆-alkyl-N(R_(7b))C(O)R_(7a), —C₀-C₆    alkyl-C(O)—C₀-C₆-alkyl-N(R₇)R_(7a),    —C₀-C₆-alkyl-C(O)N(R₇)-C₀-C₆-alkyl-N(R_(7b))R_(7a),    —C₀-C₆-alkyl-C(O)N(R₇)—C₁-C₆alkylC(O)OR_(7a), —C₀-C₆    alkyl-N(R₇)C(O)—C₀-C₆-alkyl-(R_(7a)), —C₀-C₆ alkyl    N(R₇)—C₀-C₆-alkyl-N(R_(7b))R_(7a), —C₀-C₆    alkyl-N(R₇)C(O)—C₀-C₆-alkyl-N(R_(7b))—C₀-C₆ alkyl-N(R_(7c))R_(7a),    —C₀-C₆-alkyl-N(R₇)C(O)O—C₀-C₆-alkyl-N(R_(7b))R_(7a), —C₀-C₆    alkyl-N(R₇)C(O)O—C₀-C₆-alkyl-aryl, —C₀-C₆    alkyl-C(O)N(R₇)—C₀-C₆-alkyl-N(R_(7b))R_(7a), —C₀-C₆    alkyl-N(R₇)—C₀-C₆ alkyl-C(═N(R_(7b))(R_(7a)))(NR_(7c)R_(7d)),    —C₀-C₆-alkyl-aryl, —C₀-C₆-alkyl-heteroaryl, —C₀-C₆    alkyl-heterocycloalkyl, —O—C₀-C₆ alkyl-N(R₇)R_(7a), —C₀-C₆    alkyl-OR₆, —C₀-C₆ alkyl-C(O)OR₆, C₀-C₆-alkyl-N(R₇)R_(7a), —C₀-C₆    alkyl-C(O)NR₇R_(7a), —C₀-C₆ alkyl-C(O)—R₇, —SR₇, —S(O)₂R₇, —S(O)₃R₇,    —S(O)R₇, —SO₂N(R₇)R_(7a), —SO₂N(R₇)—C₀-C₆ alkyl-N(R_(7b))R_(7a),    —S-heteroaryl, —S-aryl, —S-heterocycloalkyl,    —C₀-C₆-alkyl-N(R₇)-aryl, —C₀-C₆-alkyl-N(R₇)-heteroaryl,    —C₀-C₆-alkyl-N(R₇)-heterocycloalkyl,    —C₀-C₆-alkyl-C(O)N(R₇)—C₀-C₆-alkyl-cycloalkyl,    C₀-C₆-alkyl-C(O)N(R₇)—C₀-C₆-alkyl-aryl, C₀-C₆ alkyl-C(O)N(R₇)—C₀-C₆    alkyl-heteroaryl, C₀-C₆    alkyl-C(O)N(R₇)—C₀-C₆-alkyl-heterocycloalkyl,    —C₀-C₆-alkyl-N(R₇)C(O)—C₀-C₆-alkyl-cycloalkyl,    —C₀-C₆-alkyl-N(R₇)—C(O)—C₀-C₆-alkyl-aryl,    C₀-C₆-alkyl-N(R₇)C(O)—C₀-C₆-alkyl-heteroaryl,    —C₀-C₆-alkyl-N(R₇)C(O)—C₀-C₆-alkyl-heterocycloalkyl,    C₀-C₆-alkyl-N(R₇)C(O)—C₀-C₆-alkyl-heterocycloalkyl-aryl,    —N(R₇)C(O)OR₆, or —N(R₇)—C(O)—R_(7a), wherein each of the alkyl,    alkanyl, alkenyl, cycloalkyl, aryl, (including, for example the    alkyl within alkoxy), heterocycloalkyl, and heteroaryl groups,    either alone or as part of another group within R₃, is independently    optionally substituted with 1, 2, 3, 4, or 5 groups selected from    C₁-C₆-alkanyl, C₁-C₆-alkenyl, —C₀-C₆-alkyl-OR₉, cycloalkyl, halo,    haloalkyl, haloalkoxy, —C(O)R₉, —NO₂, —CN, oxo,    —C₀-C₆-alkyl-N(R₈)R_(8a), —C₀-C₆-alkyl-heterocycloalkyl,    —C₀-C₆-alkyl-aryl, —C₀-C₆-alkyl-heteroaryl, —C(O)OR₉, and    hydroxyalkyl;-   R₄ is hydrogen, aryl, —C₀-C₆-alkyl-N(R₇)R_(7a), C₁-C₆-alkoxy, or    C₁-C₆ alkyl, wherein each of the alkyl and aryl groups, either alone    or as part of another group in R₄, is independently optionally    substituted with 1, 2, 3, 4, or 5 groups selected from C₁-C₆-alkyl,    halo, haloalkyl, haloalkoxy, —NO₂, —CN, —OH, —N(R₈)R_(8a),    C₁-C₆-alkoxy, and —C(O)OR₆;-   R₅ is hydrogen, —C₁-C₆ alkyl-N(R₇)R_(7a), C₁-C₆-alkoxy, C₁-C₆-alkyl,    or aryl, wherein each of the alkyl and aryl is optionally    substituted with 1, 2, 3, 4, or 5 groups selected from C₁-C₆-alkyl,    halo, haloalkyl, haloalkoxy, —NO₂, —CN, —OH, —N(R₈)R_(8a), C₁-C₆    alkoxy, or —C(O)OR₆;-   R₆ and R₉ are independently hydrogen, —OH, C₁-C₆-alkyl, aryl,    arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,    heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, or aryl, each    C₁-C₆ alkyl, aryl, cycloalkyl, heterocycloalkyl, and heteroaryl,    either alone or as part of another group within R₆ and R₉, is    independently optionally substituted with 1, 2, 3, 4, or 5 groups    independently selected from —NH₂, —OH, C₁-C₆-alkoxy, C₁-C₆-alkyl,    and halo; and-   R₇, R_(7a) R_(7b), R_(7c), R_(7d), R₈, and R_(8a) are independently    hydrogen, —C₁-C₆-alkanyl, —C₁-C₆-alkenyl, —OH, —O—C₁-C₆ alkanyl,    —O—C₁-C₆ alkenyl, —O—C₀-C₆ alkyl-aryl, —C₀-C₆ alkyl-C(O)OR₆, —C₀-C₆    alkyl-C(O)R₆, aryl, arylalkyl, heteroaryl, heteroarylalkyl,    cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or    heterocycloalkylalkyl, wherein each of the alkyl, aryl, heteroaryl,    and heterocycloalkyl, either alone or part of another group within    R₇, R_(7a) R_(7b), R_(7c), and R_(7d), is independently optionally    substituted with 1, 2, 3, 4, or 5 groups selected from —NH₂,    —S—C₁-C₆ alkyl, —CN, —OH, —NO₂, C₁-C₆ alkoxy, C₁-C₆ alkyl, halo,    aryl, and heteroaryl optionally substituted with one or two C₁-C₆    alkyl.

In another embodiment, the invention comprises a pharmaceuticalcomposition comprising a PI3K inhibitor of Formula Formula VIII, VIIIa,VIIIb, or IX in combination with a compound of Formula I, Ia, Ic, Id,II, III, IV, or V and a pharmaceutically acceptable carrier, excipient,or diluent. In another embodiment, the compound is of Formula VIIIa orVIIIb.

In another embodiment, the invention provides a method of treating adisease or condition mediated by PI3K and MEK comprising administeringto a patient a PI3K compound of Formula VIII, VIIIa, VIIIb, or IX incombination with a MEK compound of Formula I, Ia, Ic, Id, II, III, IV,or V. In another embodiment, the PI3K compound is of Formula VIIIa orVIIIb. In another embodiment, the MEK Compound is of Formula Ia and thePI3K Compound is of Formula VIIIa. In another embodiment, the MEKCompound is of Formula Ia and the PI3K Compound is of Formula VIIIb. Inanother embodiment, the MEK Compound is of Formula V and the PI3KCompound is of Formula VIIIb. In another embodiment, the MEK Compound isof Section I, Embodiment G and the PI3K Compound is of VIIIb. In anotherembodiment, the MEK Compound if of Section I, Table 1 and the PI3Kcompound is of Formula VIII, VIIIa, or VIIIb.

Another embodiment of the invention is directed to suitable x-rayquality crystals, and one of ordinary skill in the art would appreciatethat they can be used as part of a method of identifying a candidateagent capable of binding to and modulating the activity of kinases. Suchmethods may be characterized by the following embodiments: a)introducing into a suitable computer program, information defining aligand binding domain of a kinase in a conformation (e.g. as defined byx-ray structure coordinates obtained from suitable x-ray qualitycrystals as described above) wherein the computer program creates amodel of the three dimensional structures of the ligand binding domain,b) introducing a model of the three dimensional structure of a candidateagent in the computer program, c) superimposing the model of thecandidate agent on the model of the ligand binding domain, and d)assessing whether the candidate agent model fits spatially into theligand binding domain. Embodiments a-d are not necessarily carried outin the aforementioned order. Such methods may further entail: performingrational drug design with the model of the three-dimensional structure,and selecting a potential candidate agent in conjunction with computermodeling.

Additionally, one skilled in the art would appreciate that such methodsmay further entail: employing a candidate agent, so-determined to fitspatially into the ligand binding domain, in a biological activity assayfor kinase modulation, and determining whether said candidate agentmodulates kinase activity in the assay. Such methods may also includeadministering the candidate agent, determined to modulate kinaseactivity, to a mammal suffering from a condition treatable by kinasemodulation, such as those described above.

Also, one skilled in the art would appreciate that compounds of theinvention can be used in a method of evaluating the ability of a testagent to associate with a molecule or molecular complex comprising aligand binding domain of a kinase. Such a method may be characterized bythe following embodiments: a) creating a computer model of a kinasebinding pocket using structure coordinates obtained from suitable x-rayquality crystals of the kinase, b) employing computational algorithms toperform a fitting operation between the test agent and the computermodel of the binding pocket, and c) analyzing the results of the fittingoperation to quantify the association between the test agent and thecomputer model of the binding pocket.

Section III Definitions

As used in the present specification, the following words and phrasesare generally intended to have the meanings as set forth below, exceptto the extent that the context in which they are used indicatesotherwise or they are expressly defined to mean something different.

The symbol “—” means a single bond, “═” means a double bond, “≡” means atriple bond,

means a single or double bond. When a group is depicted removed from itsparent Formula, the

symbol will be used at the end of the bond which was theoreticallycleaved in order to separate the group from its parent structuralFormula.

When chemical structures are depicted or described, unless explicitlystated otherwise, all carbons are assumed to have hydrogen substitutionto conform to a valence of four. For example, in the structure on theleft-hand side of the schematic below there are nine hydrogens implied.The nine hydrogens are depicted in the right-hand structure. Sometimes aparticular atom in a structure is described in textual Formula as havinga hydrogen or hydrogens as substitution (expressly defined hydrogen),for example, —CH₂CH₂—. It is understood by one of ordinary skill in theart that the aforementioned descriptive techniques are common in thechemical arts to provide brevity and simplicity to description ofotherwise complex structures.

If a group “R” is depicted as “floating” on a ring system, as forexample in the Formula:

then, unless otherwise defined, a substituent “R” may reside on any atomof the ring system, assuming replacement of a depicted, implied, orexpressly defined hydrogen from one of the ring atoms, so long as astable structure is formed.

If a group “R” is depicted as floating on a fused ring system, as forexample in the Formulae:

then, unless otherwise defined, a substituent “R” may reside on any atomof the fused ring system, assuming replacement of a depicted hydrogen(for example the —NH— in the Formula above), implied hydrogen (forexample as in the Formula above, where the hydrogens are not shown butunderstood to be present), or expressly defined hydrogen (for examplewhere in the Formula above, “X” equals ═CH—) from one of the ring atoms,so long as a stable structure is formed. In the example depicted, the“R” group may reside on either the 5-membered or the 6-membered ring ofthe fused ring system. In the Formula depicted above, when y is 2 forexample, then the two “R's” may reside on any two atoms of the ringsystem, again assuming each replaces a depicted, implied, or expresslydefined hydrogen on the ring.

When a group “R” is depicted as existing on a ring system containingsaturated carbons, as for example in the Formula:

where, in this example, “y” can be more than one, assuming each replacesa currently depicted, implied, or expressly defined hydrogen on thering; then, unless otherwise defined, where the resulting structure isstable, two “R's” may reside on the same carbon. A simple example iswhen R is a methyl group; there can exist a geminal dimethyl on a carbonof the depicted ring (an “annular” carbon). In another example, two R'son the same carbon, including that carbon, may form a ring, thuscreating a spirocyclic ring (a “spirocyclyl” group) structure with thedepicted ring as for example in the Formula:

“Acyl” means a —C(O)R radical where R is alkyl (i.e., one to ten carbonatoms of a straight, branched, or cyclic configuration, and is saturatedor unsaturated) or R is optionally substituted aryl or optionallysubstituted heteroaryl. One or more carbons in the R residue may bereplaced by nitrogen, oxygen or sulfur. Examples include acetyl,benzoyl, propionyl, isobutyryl, t-butoxycarbonyl, benzyloxycarbonyl, andpyridinylcarbonyl, and the like. Lower-acyl refers to groups containingone to six carbons.

“Acylarnino” means a —NRR′ group where R is acyl, as defined herein, andR′ is hydrogen or alkyl.

“Alkyl” means a (C₁-C₂₀) linear, branched, or cyclic hydrocarbon group(and combinations thereof, inclusively) and may be saturated orunsaturated. For example, “C₆ alkyl” may refer to an n-hexyl, iso-hexyl,cyclobutylethyl, and the like. “Lower alkyl” means an alkyl group offrom one to six carbon atoms. Examples of lower alkyl groups includemethyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, isobutyl,pentyl, hexyl and the like. A “C₀” alkyl (as in “C₀-C₆-alkyl”) is acovalent bond.

In this application, alkyl includes alkanyl, alkenyl, alkynyl, andcycloalkyl residues (and combinations thereof); it is intended toinclude cyclohexylmethyl, vinyl, allyl, isoprenyl, and the like. Thuswhen an alkyl residue having a specific number of carbons is named, allgeometric isomers having that number of carbons are intended to beencompassed; thus, for example, “C₄ alkyl” is meant to include n-butyl,sec-butyl, isobutyl, t-butyl, cyclobutyl, isobutenyl and but-2-ynylgroups; and for example, “C₃ alkyl” each include n-propyl, propenyl, andisopropyl.

“Alkanyl” means a linear saturated monovalent hydrocarbon radical of oneto twenty carbon atoms or a branched saturated monovalent hydrocarbonradical of three to 20 carbon atoms, e.g., methyl, ethyl, propyl,2-propyl, butyl (including all isomeric forms), or pentyl (including allisomeric forms), and the like. “Lower alkanyl” means alkanyl having oneto six carbons atoms.

“Cycloalkyl” means a monocyclic or polycyclic hydrocarbon radical havingthree to thirteen carbon atoms. The cycloalkyl can be saturated orpartially unsaturated, but cannot contain an aromatic ring. Cycloalkylincludes fused, bridged, and spiro ring systems. Examples of suchradicals include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.“Cycloalkylalkyl” means alkyl group substituted with one or twocycloalkyl group(s), as defined herein. Representative examples includecyclopropylmethyl and 2-cyclobutyl-ethyl, and the like.

“Optionally substituted cycloalkyl” means a cycloalkyl radical, asdefined herein, that is optionally substituted with one, two, three, orfour groups independently selected from C₁-C₆ alkanyl, C₁-C₆ alkoxy,halo, haloalkyl, haloalkoxy, oxo, hydroxy, cyano, nitro, amino,mono(C₁-C₆)alkylamino, di(C₁-C₆)alkylamino, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, amino(C₁-C₆)alkyl,mono(C₁-C₆)alkylamino(C₁-C₆)alkyl di(C₁-C₆)alkylamino(C₁-C₆)alkyl,carboxy, carboxy ester, cycloalkyl, hydroxyalkyl, —C(O)NR′R″ (where R′is hydrogen, alkyl, hydroxy, or alkoxy and R″ is hydrogen, alkyl, aryl,or heterocyclyl), optionally substituted heterocycloalkyl, optionallysubstituted heteroaryl, —NR′C(O)R″ (where R′ is hydrogen or alkyl and R″is alkyl, aryl, or heterocyclyl), and —NHS(O)₂R′ (where R′ is alkyl,aryl, or hetercyclyl).

“Alkenyl” means a straight or branched hydrocarbon radical having from 2to 20 carbon atoms and at least one double bond and includes ethenyl,propenyl, 1-but-3-enyl, 1-pent-3-enyl, 1-hex-5-enyl and the like. “Loweralkenyl” is alkenyl having 2-6 carbon atoms.

“Alkynyl” means a straight or branched hydrocarbon radical having from 2to 20 carbon atoms and at least one triple bond and includes ethynyl,propynyl, butynyl, pentyn-2-yl and the like. “Lower alkynyl” is alkynylhaving 2-6 carbon atoms.

“Alkylene” refers to straight or branched divalent hydrocarbon,containing no unsaturation and having from one to ten carbon atoms.Examples of alkylene include methylene (—CH₂—), ethylene (—CH₂CH₂—),propylene (—CH₂CH₂CH₂—), and dimethylpropylene (—CH₂C(CH₃)₂CH₂—), andthe like.

“Alkylidyne” or “alkynylene” means a straight or branched divalenthydrocarbon having from two to ten carbon atoms, and containing at leastone triple bond, for example, propylid-2-ynyl, n-butylid-1-ynyl, and thelike.

“Alkoxy” or “alkoxyl” means —O-alkyl, where the alkyl group includesfrom one to eight carbon atoms of a straight, branched, cyclicconfiguration, unsaturated chains, and combinations thereof attached tothe parent structure through an oxygen atom. Examples include metboxy,ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like.Lower-alkoxy refers to groups containing one to six carbons.

“Alkylamino” means a —NHR radical where R is alkyl as defined herein, oran N-oxide derivative, or a protected derivative thereof, e.g.,methylamino, ethylamino, n-, iso-propylamino, n-, iso-, tert-butylamino,or methylamino-N-oxide, and the like.

“Alkylaminoalkyl” means an alkyl group substituted with one or twoalkylamino groups, as defined herein.

“Aryl” means a monovalent six- to fourteen-membered, mono- orbi-carbocyclic ring, wherein the monocyclic ring is aromatic and atleast one of the rings in the bicyclic ring is aromatic. Representativeexamples include phenyl, naphthyl, and indanyl, and the like.

“Optionally substituted aryl” means an aryl group, as defined herein,which is optionally substituted with one, two, three, four, of fivegroups selected from halo, haloalkyl, haloalkoxy, hydroxy, loweralkanyl, lower alkenyl, lower alkynyl, alkoxy, carboxy, carboxy ester,amino, alkylamino, dialkylamino, optionally substituted cycloalkyl,optionally substituted heterocycloalkyi, optionally substitutedheteroaryl, —C(O)NR′R″ (where R′ is hydrogen or alkyl and R″ ishydrogen, alkyl, aryl, or heterocyclyl), —NR′C(O)R″ (where R′ ishydrogen or alkyl and R″ is alkyl, aryl, or heterocyclyl), and—NHS(O)₂R′ (where R′ is alkyl, aryl, or heteroaryl).

“Arylalkyl” means a residue in which an aryl moiety is attached to aparent structure via one of an alkylene, alkylidene, or alkylidynegroup. Examples include benzyl, phenethyl, phenylvinyl, phenylallyl andthe like. “Lower arylalkyl” refers to an arylalkyl where the “alkyl”portion of the group has one to six carbons; this can also be referredto as C₁₋₆ arylalkyl. When a group is referred to as “C₁-C₆ alkyl-aryl”or “C₀-C₆ alkyl-aryl”, an aryl moiety is attached to a parent structurevia an alkylene group. Examples include benzyl, phenethyl, and the like.

“Arylalkyloxy” means an —OR group where R is arylalkyl, as definedherein.

“Carboxy ester” means a —C(O)OR group where R is lower alkanyl, loweralkenyl, lower alkynyl, cycloalkyl, aryl or arylalkyl, each of which isdefined herein. Representative examples include methoxycarbonyl,ethoxycarbonyl, and benzyloxycarbonyl, and the like.

“Dialkylamino” means a —NRR′ radical where R and R′ are independentlyalkyl as defined herein, or an N-oxide derivative, or a protectedderivative thereof, e.g., dimethylami no, diethylamino,N,N-methylpropylamino or N,N-methylethylamino, and the like.

“Fused-polycyclic” or “fused ring system” refers to a polycyclic ringsystem that contains bridged or fused rings; that is, where two ringshave more than one shared atom in their ring structures. In thisapplication, fused-polycyclics and fused ring systems are notnecessarily all aromatic ring systems. Typically, but not necessarily,fused-polycyclics share a vicinal set of atoms, for example naphthaleneor 1,2,3,4-tetrahydro-naphthalene. A spiro ring system is not afused-polycyclic by this definition, but fused polycyclic ring systemsof the invention may themselves have spiro rings attached thereto via asingle ring atom of the fused-polycyclic. In some examples, asappreciated by one of ordinary skill in the art, two adjacent groups onan aromatic system may be fused together to form a ring structure. Thefused ring structure may contain heteroatoms and may be optionallysubstituted with one or more groups. It should additionally be notedthat saturated carbons of such fused groups (i.e. saturated ringstructures) can contain two substitution groups.

“Haloaloxy” means an —OR′ group where R′ is haloalkyl as defined herein,e.g., trifluoromethoxy or 2,2,2-trifluoroethoxy, and the like.

“Halogen” or “halo” means fluoro, chloro, bromo or iodo.

“Haloalkyl” and “haloaryl” mean an alkyl and an aryl group,respectively, that are substituted with one or more halogens, preferablyone to five halo atoms. Thus, “dihaloaryl,” “dihaloalkyl,” and“trihaloaryl” etc. refer to aryl and alkyl substituted with a pluralityof halogens, but not necessarily a plurality of the same halogen; thus4-chloro-3-fluorophenyl is within the scope of dihaloaryl.

“Heteroatom” refers to O, S, N, or P.

“Heterocyclyl” refers to a stable three- to fifteen-membered ringsubstituent that consists of carbon atoms and from one to fivebeteroatoms selected from the group consisting of nitrogen, phosphorus,oxygen and sulfur. For purposes of this invention, the heterocyclylsubstituent may be a monocyclic, bicyclic or tricyclic ring system,which may include fused or bridged ring systems as well as spirocyclicsystems. The terms “heterocycloalkyl” and “heteroaryl” are groups thatare encompassed by the broader term “heterocyclyl.” The nitrogen,phosphorus, carbon or sulfur atoms in the heterocyclyl group may beoptionally oxidized to various oxidation states. In a specific example,the group —S(O)₀₋₂—, refers to —S— (sulfide), —S(O)— (sulfoxide), and—SO₂— (sulfone). For convenience, nitrogens, particularly but notexclusively, those defined as annular aromatic nitrogens, are meant toinclude their corresponding N-oxide form, although not explicitlydefined as such in a particular example. Thus, for a compound of theinvention having, for example, a pyridyl ring; the correspondingpyridyl-N-oxide is meant to be included as another compound of theinvention. In addition, annular nitrogen atoms may be optionallyquatemized; and the ring substituent may be partially or fully saturatedor aromatic. Examples of heterocyclyl groups include, but are notlimited to, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl,benzofuranyl, carbazoyl, cinnolinyl, dioxolanyl, indolizinyl,naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl,phenoxazinyl, phthalazinyl, pteridinyl, purinyl, quinazolinyl,quinoxalinyl, quinolinyl, isoquinolinyl, tetrazoyl,tetrahydroisoquinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl,4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl,imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl,oxazolidinyl, triazolyl, isoxazolyl, isoxazolidinyl, morpholinyl,thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl,isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl,octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl,decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl,benzothiazolyl, benzoxazolyl, firyl, tetrahydrofuryl, tetrahydropyranyl,thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide,thiamorpholinyl sulfone, dioxaphospholanyl, oxadiazolyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, and tetrahydroquinolinyl.

“Optionally substituted heterocyclyl” means a heterocyclyl group, asdefined herein, optionally substituted with one, two, three, four, orfive groups selected from halo, haloalkyl, haloalkoxy, hydroxy, oxo(valency rules permitting), lower alkanyl, lower alkenyl, lower alkynyl,alkoxy, optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, optionally substitutedheteroaryl, alkylaminoalkyl, dialkylaminoalkyl, carboxy, carboxy ester,—C(O)NR′R″ (where R′ is hydrogen or alkyl and R″ is hydrogen, alkyl,aryl, or heterocyclyl), —NR′C(O)R″ (where R′ is hydrogen or alkyl and R″is alkyl, aryl, or heterocyclyl), amino, alkylamino, dialkylamino, and—NHS(O)₂R′ (where R′ is alkyl, aryl, or heteroaryl).

“Heteroalicyclic” and “heterocycloalkyl” mean a non-aromaticheterocyclyl group, as defined herein. A “heteroalicyclic” or“heterocycloalkyl” may be fully saturated or may contain unsaturation,but is not aromatic. “Heteroalicyclic” or “heterocycloalkyl” may bemonocyclic or bicyclic (including fused, bridged, and spiro ringsystems).

“Optionally substituted heteroalicyclic” and “optionally substitutedheterocycloalkyl” mean, respectively, a heteroalicyclic andheterocycloalkyl ring, each as defined herein, optionally substitutedwith one, two, three, four, or five groups selected from halo,haloalkyl, haloalkoxy, hydroxy, oxo, lower alkanyl, lower alkenyl, loweralkynyl, alkoxy, optionally substituted cycloalkyl, heterocycloalkyl,optionally substituted aryl, optionally substituted heteroaryl,alkylaminoalkyl, dialkylaminoalkyl, carboxy, carboxy ester, —C(O)NR′R″(where R′ is hydrogen or alkyl and R″ is hydrogen, alkyl, aryl, orbeterocyclyl), —NR′C(O)R″ (where R′ is hydrogen or alkyl and R″ isalkyl, aryl, or beterocyclyl), amino, alkylamino, dialkylamino, and—NHS(O)₂R′ (where R′ is alkyl, aryl, or heteroaryl).

“Heteroaryl” means a 5- to 12-membered, monocyclic aromatic heterocyclyl(where heterocyclyl is defined herein) or bicyclic heterocyclyl ringsystem (where at least one of the rings in the bicyclic system isaromatic) where the monocyclic ring and at least one of the rings in thebicyclic ring system contains one, two, three, four, or fiveheteroatom(s) selected from nitrogen, oxygen, phosphorous, and sulfur.Representative examples include pyridinyl, imidazolyl, pyrimidinyl,pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl,thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl,indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl,indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl,pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl,furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl,benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, andfuropyridinyl. Fused, bridged, and spiro moieties are also includedwithin the scope of this definition.

“Optionally substituted heteroaryl” means a heteroaryl group, as definedherein, optionally substituted with one, two, three, four, or fivegroups selected from halo, haloalkyl, haloalkoxy, lower alkanyl, loweralkenyl, lower alkynyl, alkoxy, hydroxy, oxo (valency rules permitting),carboxy, carboxy ester, amino, alkylamino, dialkylamino, optionallysubstituted cycloalkyl, optionally substituted heterocycloalkyl,heteroaryl, optionally substituted aryl, —C(O)NR′R″ (where R′ ishydrogen or alkyl and R″ is hydrogen, alkyl, aryl, or heterocyclyl),—NR′C(O)R″ (where R′ is hydrogen or alkyl and R″ is alkyl, aryl, orheterocyclyl), and —NHS(O)₂R′ (where R′ is alkyl, aryl, or heteroaryl).

“Optionally substituted heterocyclylalkyl” means an alkyl groupsubstituted with an optionally substituted heterocyclyl group, asdefined herein. Examples include (4-methylpiperazin-1-yl)methyl,(morpholin-4-yl)methyl, (pyridin-4-yl)methyl, 2-(oxazolin-2-yl)ethyl,4-(4-methylpiperazin-1-yl)-2-butenyl, and the like. In addition, thealkyl portion of a heterocyclylalkyl group may be substituted asdescribed in the definition for “substituted”. “Lower heterocyclylalkyl”means a heterocyclylalkyl where the “alkyl” portion of the group has oneto six carbons. “Heteroalicyclylalkyl” or “lower heterocycloalkylalkyl”means a heterocyclylalkyl where the heterocyclyl portion of the group isnon-aromatic; and “heteroarylalkyl” means a heterocyclylalkyl where theheterocyclyl portion of the group contains an aromatic ring. Such termsmay be described in more than one way, for example, “lowerheterocyclylalkyl” and “heterocyclyl C₁₋₆alkyl” are equivalent terms.Additionally, for simplicity, the number of annular atoms (includingheteroatoms) in a heterocycle may be denoted as “C_(x)-C_(y)” (as in“C_(x)-C_(y)-heterocyclyl” and “C_(x)-C_(y)-heteroaryl” (and the like)),where x and y are integers. So, for example, C₅-C₁₄-heterocyclyl refersto a 5 to 14 membered ring system having at least one heteroatom and nota ring system containing 5 to 14 annular carbon atoms.

“Hydroxyalkyl” means an alkanyl, alkenyl, or alkynyl radical, as definedherein, substituted with at least one, preferably one, two, or three,hydroxy group(s), provided that if two hydroxy groups are present theyare not both on the same carbon atom. Representative examples include,but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl,3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl,3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl,1-(hydroxymethyl)-2-bydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyland 2-(hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl,2,3-dihydroxypropyl, or 1-(hydroxymethyl)-2-hydroxyethyl, and the like.

“Optional” or “optionally” means that the subsequently described eventor circumstance may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not. One of ordinary skill in the art would understand that withrespect to any molecule described as containing one or more optionalsubstituents, only sterically practical and/or synthetically feasiblecompounds are meant to be included. “Optionally substituted” refers toall subsequent modifiers in a term. So, for example, in the term“optionally substituted arylC₁₋₈ alkyl,” both the “C₁₋₈ alkyl” portionand the “aryl” portion of the molecule may or may not be substituted. Alist of exemplary optional substitutions is presented below in thedefinition of “substituted.”

“Saturated bridged ring system” refers to a bicyclic or polycyclic ringsystem that is not aromatic. Such a system may contain isolated orconjugated unsaturation, but not aromatic or heteroaromatic rings in itscore structure (but may have aromatic substitution thereon). Forexample, hexahydro-furo[3,2-b]furan, 2,3,3a,4,7,7a-hexahydro-1H-indene,7-aza-bicyclo[2.2.1]heptane, and 1,2,3,4,4a,5,8,8a-octahydro-naphthaleneare all included in the class “saturated bridged ring system.”

“Spirocyclyl” or “spirocyclic ring” refers to a ring originating from aparticular annular carbon of another ring. For example, as depictedbelow, a ring atom of a saturated bridged ring system (rings B and B′),but not a bridgehead atom, can be a shared atom between the saturatedbridged ring system and a spirocyclyl (ring A) attached thereto. Aspirocyclyl can be carbocyclic or heteroalicyclic.

“Substituted” alkyl, alkylene, alkylidene, and alkylidyne referrespectively to alkyl, alkylene, alkylidene, and alkylidyne where one ormore (for example up to about five, in another example, up to aboutthree) hydrogen atoms are replaced by a substituent independentlyselected from halo, optionally substituted aryl, hydroxy, alkoxy,optionally substituted heterocyclyl, alkylenedioxy, amino, alkylamino,dialkylamino), amidino, aryloxy, arylalkyloxy, carboxy, carboxy ester,alkylcarbonyloxy, carbamyl, alkylaminocarbonyl, dialkylaminocarbonyl,benzyloxycarbonylamino (CBZ-amino), cyano, acyl, nitro, S(O)_(n1)R′(where n1 is 0, 1, or 2 and R′ is alkyl, substituted alkyl, optionallysubstituted aryl, optionally substituted heterocycloalkyl, or optionallysubstituted heteroaryl), oxo, acylamino, and sulfonamido.

“Sulfonamido” means a —NRSO₂R′ or —SO₂NRR″ group where R is hydrogen orlower alkyl, R′ is lower alkanyl, lower alkenyl, optionally substitutedaryl, optionally substituted heterocycloalkyl, optionally substitutedcycloalkyl, or optionally substituted heteroaryl, and R″ is hydrogen orR′.

Representative compounds from Section III are depicted below. Theexamples are merely illustrative and do not limit the scope of theinvention in any way. Compounds of the invention are named according tosystematic application of the nomenclature rules agreed upon by theInternational Union of Pure and Applied Chemistry (IUPAC), InternationalUnion of Biochemistry and Molecular Biology (IUBMB), and the ChemicalAbstracts Service (CAS).

TABLE 1 Cpd. No. Structure IUPAC Name 1

N-(4-{[(3-{[4- (methyloxy)phenyl]amino}quinoxalin-2- yl)amino]sulfonyl}phenyl)acetamide 2

4-bromo-N-[3-(phenylamino)quinoxalin-2- yl] benzene sulfonamide 3

4-bromo-N-{3-[(2- methylphenyl)amino]quinoxalin-2- yl}benzenesulfonamide 4

N-(3-{[4- (methyloxy)phenyl]amino}quinoxalin-2-yl) benzene sulfonamide 5

4-bromo-N-(3-{[4- (methyloxy)phenyl]amino}quinoxalin-2-yl) benzenesulfonamide 6

4-chloro-N-[6-(methyloxy)-3-{[3- (methyloxy)phenyl]amino}quinoxalin-2-yl]benzenesulfonamide 7

4-chloro-N-{3-[(4-chlorophenyl)amino]-6- (methyloxy)quinoxalin-2-yl}benzenesulfonamide 8

N-(4-{[3-{[(4- chlorophenyl)sulfonyl]amino}-7-(methyloxy)quinoxalin-2-yl]amino}phenyl) acetamide 9

4-chloro-N-{6-(methyloxy)-3-[(2-oxo-2,3- dihydro-1H-benzimidazol-5-yl)amino]quinoxalin-2- yl}benzenesulfonamide 10

N-{4-[(3-{[(4- chlorophenyl)sulfonyl]amino}quinoxalin-2- yl)amino]phenyl}acetamide 11

N-(3-{[4- (ethyloxy)phenyl]amino}quinoxalin-2-yl)-4- methylbenzenesulfonamide 12

N-{3-[(3,4-dimethylphenyl)amino]-6-methylquinoxalin-2-yl}-4-methylbenzene sulfonamide 13

N-(3-{[3- (dimethylamino)phenyl]amino}quinoxalin-2- yl)-4-methylbenzenesulfonamide 14

N-(3-{[4- (ethyloxy)phenyl]amino}quinoxalin-2- yl)benzene sulfonamide 15

4-methyl-N-(3-{[4- (methyloxy)phenyl]amino}quinoxalin-2-yl) benzenesulfonamide 16

4-methyl-N-{6-methyl-3-[(4- methylphenyl)amino]quinoxalin-2- yl}benzenesulfonamide 17

N-{3-[(4-hydroxyphenyl)amino]-6- methylquinoxalin-2-yl}-4-methylbenzenesulfonamide 18

4-methyl-N-(3-morpholin-4-ylquinoxalin-2- yl)benzenesulfonamide 19

N-{3-[(2,5- dimethylphenyl)amino]quinoxalin-2-yl}-4-methylbenzenesulfonamide 20

4-chloro-N-[3-(naphthalen-2- ylamino)quinoxalin-2-yl]benzenesulfonamide21

N-{3-[(3-aminophenyl)amino]quinoxalin-2- yl}-4-chlorobenzenesulfonamide22

N-(3-{[4- (aminosulfonyl)phenyl]amino}quinoxalin-2-yl)-3-nitrobenzenesulfonamide 23

4-chloro-N-{3-[(4- chlorophenyl)amino]quinoxalin-2-yl}benzenesulfonamide 24

4-chloro-N-{3-[(4- methylphenyl)amino]quinoxalin-2-yl}benzenesulfonamide 25

4-chloro-N-{3-[(2- methylphenyl)amino]quinoxalin-2-yl}benzenesulfonamide 26

methyl 4-[(3-{[(4- chlorophenyl)sulfonyl]amino}quinoxalin-2- yl)amino]benzoate 27

methyl 2-chloro-5-[(3-{[(4- methylphenyl)sulfonyl]amino}quinoxalin-2-yl) amino]benzoate 28

N-{4-[(7-methyl-3-{[(4- methylphenyl)sulfonyl]amino}quinoxalin-2- yl)amino]phenyl}acetamide 29

4-methyl-N-(6-methyl-3-{[2- (methyloxy)phenyl]amino} quinoxalin-2-yl)benzenesulfonamide 30

5,12-bis[(4-methylphenyl) sulfonyl]-5,12-dihydroquinoxalino[2,3-b]quinoxaline 31

N-[3-(phenylamino)quinoxalin-2- yl]benzenesulfonamide 32

N-{3-[(4-chlorophenyl)amino]quinoxalin-2- yl}benzenesulfonamide 33

N-{3-[(phenylmethyl)amino]quinoxalin-2- yl}benzenesulfonamide 34

4-({3-[(phenylsulfonyl)amino]quinoxalin-2- yl}amino)benzoic acid 35

3-({3-[(phenylsulfonyl)amino]quinoxalin-2- yl}amino)benzenesulfonamide36

N-{3-[(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)amino]quinoxalin- 2-yl}benzenesulfonamide 37

N-[3-(1H-benzimidazol-1-yl)quinoxalin-2- yl]benzenesulfonamide 38

N-{3-[(4-hydroxyphenyl)amino]quinoxalin- 2-yl}benzenesulfonamide 39

N-[3-(naphthalen-2-ylamino)quinoxalin-2- yl]benzenesulfonamide 40

N-{3-[(4-hydroxyphenyl)amino]quinoxalin-2-yl}-4-methylbenzenesulfonamide 41

N-(3-{[4- (aminosulfonyl)phenyl]amino}quinoxalin-2-yl)-4-methylbenzenesulfonamide 42

3-[(3-{[(4- methylphenyl)sulfonyl]amino}quinoxalin-2- yl)amino]benzoicacid 43

N-[4-({[3-(phenylamino)quinoxalin-2- yl]amino}sulfonyl)phenyl]acetamide44

N-(4-{[(3-{[4- (aminosulfonyl)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)acetamide 45

N-[4-({[3-(naphthalen-1-ylamino)quinoxalin-2-yl]amino}sulfonyl)phenyl]acetamide 46

N-{4-[(3-{[(4- methylphenyl)sulfonyl]amino}quinoxalin-2-yl)amino]phenyl}acetamide 47

N-(3-{[3- (aminosulfonyl)phenyl]amino}quinoxalin-2-yl)-4-bromobenzenesulfonamide 48

N-{3-[(3-hydroxyphenyl)amino]quinoxalin-2-yl}-4-methylbenzenesulfonamide 49

N-{3-[(2-ethylphenyl)amino]quinoxalin-2- yl}benzenesulfonamide 50

4-chloro-N-(3-{[4- (methyloxy)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide 51

4-chloro-N-(3-{[2- (methyloxy)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide 52

4-[(3-{[(4- chlorophenyl)sulfonyl]amino}quinoxalin-2-yl)amino]-2-hydroxybenzoic acid 53

N-(3-{[4- (methyloxy)phenyl]amino}quinoxalin-2-yl)-3-nitrobenzenesulfonamide 54

3-[(3-{[(4- chlorophenyl)sulfonyl]amino}quinoxalin-2- yl)amino]benzoicacid 55

N-(3-{[4- (aminosulfonyl)phenyl]amino}quinoxalin-2-yl)-4-chlorobenzenesulfonamide 56

N-(3-{[3- (aminosulfonyl)phenyl]amino}quinoxalin-2-yl)-4-chlorobenzenesulfonamide 57

N-[3-(naphthalen-2-ylamino)quinoxalin-2- yl]-4-nitrobenzenesulfonamide58

N-(3-{[3- (methyloxy)phenyl]amino}quinoxalin-2- yl)benzenesulfonamide 59

N-{3-[(4-bromophenyl)amino]quinoxalin-2- yl}-3-nitrobenzenesulfonamide60

3-[(3-{[(4- nitrophenyl)sulfonyl]amino}quinoxalin-2- yl)amino]benzoicacid 61

4-nitro-N-[3-(phenylamino)quinoxalin-2- yl]benzenesulfonamide 62

4-chloro-N-[3-(phenylamino)quinoxalin-2- yl]benzenesulfonamide 63

3-nitro-N-[3-(phenylamino)quinoxalin-2- yl]benzenesulfonamide 64

4-[(3-{[(4- nitrophenyl)sulfonyl]amino}quinoxalin-2- yl)amino]benzoicacid 65

N-[3-(naphthalen-2-ylamino)quinoxalin-2- yl]-3-nitrobenzenesulfonamide66

4-methyl-N-(3-{[3- (methyloxy)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide 67

N-(3-{[3-chloro-4- (methyloxy)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide 68

N-{3-[(3-chloro-4- fluorophenyl)amino]quinoxalin-2-yl}benzenesulfonamide 69

methyl 2-chloro-5-({3- [(phenylsulfonyl)amino]quinoxalin-2-yl}amino)benzoate 70

4-chloro-N-{3-[(3- hydroxyphenyl)amino]quinoxalin-2-yl}benzenesulfonamide 71

4-methyl-N-[6-methyl-3- (phenylamino)quinoxalin-2- yl]benzenesulfonamide72

N-{4-[({3-[(4- methylphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]phenyl}acetamide 73

1-methylethyl 4-[(3-{[(4- chlorophenyl)sulfonyl]amino}-7-methylquinoxalin-2-yl)amino]benzoate 74

N-(3-{[2- (methyloxy)phenyl]amino}quinoxalin-2- yl)benzenesulfonamide 75

N-{3-[(4-methylphenyl)amino]quinoxalin-2- yl}benzenesulfonamide 76

N-{3-[(3-methylphenyl)amino]quinoxalin-2- yl}benzenesulfonamide 77

N-{3-[(4-bromophenyl)amino]quinoxalin-2- yl}-4-methylbenzenesulfonamide78

4-methyl-N-{3-[(3- methylphenyl)amino]quinoxalin-2-yl}benzenesulfonamide 79

4-methyl-N-[3-(naphthalen-1- ylamino)quinoxalin-2-yl]benzenesulfonamide80

N-{4-[({3-[(4- chlorophenyl)amino]quinoxalin-2-yl}amino)sulfonyl]phenyl}acetamide 81

N-(4-{[(3-{[3- (aminosulfonyl)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)acetamide 82

4-methyl-N-{3- [(phenylmethyl)amino]quinoxalin-2- yl}benzenesulfonamide83

4-[(3-{[(4- bromophenyl)sulfonyl]amino}quinoxalin-2-yl)amino]-2-hydroxybenzoic acid 84

4-bromo-N-{3-[(4- methylphenyl)amino]quinoxalin-2- yl}benzenesulfonamide85

4-bromo-N-{3-[(3- methylphenyl)amino]quinoxalin-2- yl}benzenesulfonamide86

N-{4-[({3-[(2- hydroxyethyl)amino]quinoxalin-2-yl}amino)sulfonyl]phenyl}acetamide 87

4-bromo-N-[3-(naphthalen-1- ylamino)quinoxalin-2-yl]benzenesulfonamide88

N-(3-{[3- (trifluoromethyl)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide 89

4-[(3-{[(4- chlorophenyl)sulfonyl]amino}quinoxalin-2- yl)amino]benzoicacid 90

3-[(3-{[(3- nitrophenyl)sulfonyl]amino}quinoxalin-2- yl)amino]benzoicacid 91

N-{3-[(2-methylphenyl)amino]quinoxalin-2- yl}benzenesulfonamide 92

4-({3-[(phenylsulfonyl)amino]quinoxalin-2- yl}amino)benzenesulfonamide93

N-[3-(naphthalen-1-ylamino)quinoxalin-2- yl]-3-nitrobenzenesulfonamide94

N-(3-{[3- (aminosulfonyl)phenyl]amino}quinoxalin-2-yl)-3-nitrobenzenesulfonamide 95

N-{3-[(4-bromophenyl)amino]quinoxalin-2- yl}-4-nitrobenzenesulfonamide96

4-chloro-N-[3-(naphthalen-1- ylamino)quinoxalin-2-yl]benzenesulfonamide97

N-{4-[({3-[(phenylmethyl)amino]quinoxalin-2-yl}amino)sulfonyl]phenyl}acetamide 98

N-[4-({[3-(butylamino)quinoxalin-2- yl]amino}sulfonyl)phenyl]acetamide99

N-[3-(butylamino)quinoxalin-2-yl]-4- methylbenzenesulfonamide 100

N-[3-(cyclohexylamino)quinoxalin-2- yl]benzenesulfonamide 101

1-(phenylsulfonyl)-3-[4-(pyrrolidin-1-ylsulfonyl)phenyl]-2,3-dihydro-1H- imidazo[4,5-b]quinoxaline 102

1-(phenylsulfonyl)-3-[4-(piperidin-1- ylsulfonyl)phenyl]-2,3-dihydro-1H-imidazo[4,5-b]quinoxaline 103

2,5-dichloro-N-[3-(3,4-dihydroquinolin- 1(2H)-yl)quinoxalin-2-yl]benzenesulfonamide 104

ethyl 2-[(3-{[(4- methylphenyl)sulfonyl]amino}quinoxalin-2-yl)amino]-4,5,6,7-tetrahydro-1- benzothiophene-3-carboxylate 105

2,5-dichloro-N-{3-[(2-morpholin-4- ylphenyl)amino]quinoxalin-2-yl}benzenesulfonamide 106

N-{4-[({3-[(3- methylphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]phenyl}acetamide 107

4-chloro-N-{3-[(3-chloro-4-piperidin-1-ylphenyl)amino]-6-methylquinoxalin-2- yl}benzenesulfonamide 108

3-nitro-N-[3-(quinolin-6-ylamino)quinoxalin- 2-yl]benzenesulfonamide 109

butyl N-{[4-({3- [(phenylsulfonyl)amino]quinoxalin-2-yl}amino)phenyl]carbonyl}glycinate 110

4-nitro-N-(3-{[3- (trifluoromethyl)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide 111

N-[4-({3-[(phenylsulfonyl)amino]quinoxalin- 2-yl}amino)phenyl]acetamide112

N-{3-[(3-{[(4- methylphenyl)sulfonyl]amino}quinoxalin-2-yl)amino]phenyl}acetamide 113

ethyl 3,3,3-trifluoro-2-hydroxy-2-{4-[(3- {[(4-methylphenyl)sulfonyl]amino}quinoxalin-2- yl)amino]phenyl}propanoate 114

N-{3-[(4-{[(2,6-dimethylpyrimidin-4-yl)amino]sulfonyl}phenyl)amino]quinoxalin-2-yl}-3-nitrobenzenesulfonamide 115

4-chloro-N-{3-[(3,4-dimethylphenyl)amino]- 6-methylquinoxalin-2-yl}benzenesulfonamide 116

4-chloro-N-(6-methyl-3-{[3- (methyloxy)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide 117

butyl 4-[(3-{[(4- chlorophenyl)sulfonyl]amino}-7-methylquinoxalin-2-yl)amino]benzoate 118

4-chloro-N-{3-[(3-chloro-4- methylphenyl)amino]quinoxalin-2-yl}benzenesulfonamide 119

1-methylethyl 4-[(3-{[(4- chlorophenyl)sulfonyl]amino}quinoxalin-2-yl)amino]benzoate 120

N-{3-[(2,5-dimethylphenyl)amino]-6- nitroquinoxalin-2-yl}-4-methylbenzenesulfonamide 121

N-[3-(cyclohexylamino)-6-nitroquinoxalin-2-yl]-4-methylbenzenesulfonamide 122

N-{3-[(2,4- dimethylphenyl)amino]quinoxalin-2-yl}-4-methylbenzenesulfonamide 123

N-(3-{[4-(ethyloxy)phenyl]amino}-6- methylquinoxalin-2-yl)-4-methylbenzenesulfonamide 124

3-({3-[({4- [hydroxy(oxido)amino]phenyl}sulfonyl)amino]quinoxalin-2-yl}amino)benzoic acid 125

N-{[4-({3- [(phenylsulfonyl)amino]quinoxalin-2-yl}amino)phenyl]carbonyl}glycine 126

4-chloro-N-[3-({2- [(difluoromethyl)oxy]phenyl}amino)quinoxalin-2-yl]benzenesulfonamide 127

N-{3-[(3-{[(4- chlorophenyl)sulfonyl]amino}-7- methylquinoxalin-2-yl)amino]phenyl}acetamide 128

4-chloro-N-{3-[(3,5-dimethyl-1H-pyrazol-4-yl)amino]-6-methylquinoxalin-2- yl}benzenesulfonamide 129

4-bromo-N-{3-[(4′-nitrobiphenyl-3- yl)amino]quinoxalin-2-yl}benzenesulfonamide 130

4-bromo-N-{3-[(2- chlorophenyl)amino]quinoxalin-2- yl}benzenesulfonamide131

N-{3-[(4-butylphenyl)amino]-6- methylquinoxalin-2-yl}-4-chlorobenzenesulfonamide 132

N-{4-[(3-{[(4- chlorophenyl)sulfonyl]amino}-7- methylquinoxalin-2-yl)amino]phenyl}acetamide 133

4-chloro-N-{6-methyl-3-[(2-oxo-2,3- dihydro-1H-benzimidazol-5-yl)amino]quinoxalin-2- yl}benzenesulfonamide 134

propyl 4-[(3-{[(4- chlorophenyl)sulfonyl]amino}-7-methylquinoxalin-2-yl)amino}benzoate 135

4-chloro-N-{3-[(4- fluorophenyl)amino]quinoxalin-2-yl}benzenesulfonamide 136

N-[4-({[3-(naphthalen-2-ylamino)quinoxalin-2-yl]amino}sulfonyl)phenyl]acetamide 137

4-bromo-N-(3-{[4- (phenylamino)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide 138

2-hydroxy-4-({3- [(phenylsulfonyl)amino]quinoxalin-2- yl}amino)benzoicacid 139

N-(3-{[3- (aminosulfonyl)phenyl]amino}quinoxalin-2-yl)-4-methylbenzenesulfonamide 140

4-[(3-{[(3- nitrophenyl)sulfonyl]amino}quinoxalin-2- yl)amino]benzoicacid 141

N-(3-{[3- (butyloxy)phenyl]amino}quinoxalin-2-yl)-4-methylbenzenesulfonamide 142

N-{3-[(4-fluorophenyl)amino]quinoxalin-2- yl}-3-nitrobenzenesulfonamide143

4-{[3-({[4- (acetylamino)phenyl]sulfonyl}amino)quinoxalin-2-yl]amino}-2-hydroxybenzoic acid 144

N-(3-{[4- (butyloxy)phenyl]amino}quinoxalin-2-yl)-4-chlorobenzenesulfonamide 145

N-[3-(naphthalen-1-ylamino)quinoxalin-2- yl]-4-nitrobenzenesulfonamide146

4-[(3-{[(4- bromophenyl)sulfonyl]amino}quinoxalin-2- yl)amino]benzoicacid 147

N-{4-[({3-[(3- hydroxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]phenyl}acetamide 148

3-[(3-{[(4- bromophenyl)sulfonyl]amino}quinoxalin-2- yl)amino]benzoicacid 149

4-bromo-N-(3-{[3- (butyloxy)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide 150

4-bromo-N-(3-{[3- (trifluoromethyl)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide 151

4-methyl-N-{3-[(4′-nitrobiphenyl-3- yl)amino]quinoxalin-2-yl}benzenesulfonamide 152

4-chloro-N-{3-[(3- fluorophenyl)amino]quinoxalin-2-yl}benzenesulfonamide 153

N-{3-[(2-chlorophenyl)amino]quinoxalin-2- yl}benzenesulfonamide 154

4-bromo-N-[3-(quinolin-5- ylamino)quinoxalin-2-yl]benzenesulfonamide 155

N-{3-[(3-fluorophenyl)amino]quinoxalin-2- yl}-4-methylbenzenesulfonamide156

N-{3-[(4-fluorophenyl)amino]quinoxalin-2- yl}-4-methylbenzenesulfonamide157

3-nitro-N-(3-{[3- (trifluoromethyl)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide 158

2-hydroxy-4-[(3-{[(3- nitrophenyl)sulfonyl]amino}quinoxalin-2-yl)amino]benzoic acid 159

N-{3-[(3-chlorophenyl)amino]quinoxalin-2- yl}-4-methylbenzenesulfonamide160

N-[3-(1,3-benzodioxol-5- ylamino)quinoxalin-2-yl]-4-bromobenzenesulfonamide 161

N-{3-[(3-acetylphenyl)amino]quinoxalin-2- yl}-4-chlorobenzenesulfonamide162

3-nitro-N-(3-{[4-(9H-xanthen-9- yl)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide 163

4-chloro-N-{3-[(4′-nitrobiphenyl-3- yl)amino]quinoxalin-2-yl}benzenesulfonamide 164

N-[3-(2,1,3-benzothiadiazol-5-ylamino)quinoxalin-2-yl]-4-tolylsulfonamide 165

N-{3-[(2-methyl-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl)amino]quinoxalin-2- yl}benzenesulfonamide 166

4-methyl-N-[3-(quinolin-5- ylamino)quinoxalin-2-yl]benzenesulfonamide167

4-methyl-N-{3-[(1-oxo-1,3-dihydro-2- benzofuran-5-yl)amino]quinoxalin-2-yl}benzenesulfonamide 168

4-chloro-N-{3-[(2- chlorophenyl)amino]quinoxalin-2-yl}benzenesulfonamide 169

2-hydroxy-5-[(3-{[(4- methylphenyl)sulfonyl]amino}quinoxalin-2-yl)amino]benzoic acid 170

N-(3-{[3,5-bis(1,1-dimethylethyl)-4- hydroxyphenyl]amino}quinoxalin-2-yl)benzenesulfonamide 171

N-[3-({2- [(trifluoromethyl)thio]phenyl}amino)quinoxalin-2-yl]benzenesulfonamide 172

N-{4-[({3-[(4- hydroxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]phenyl}acetamide 173

N-[3-(1,3-benzodioxol-5- ylamino)quinoxalin-2-yl]-4-methylbenzenesulfonamide 174

N-(3-{[2,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide 175

N-{3-[(2,4- dichlorophenyl)amino]quinoxalin-2- yl}benzenesulfonamide 176

N-[4-({[3-(2,3-dihydro-1,4-benzodioxin-6- ylamino)quinoxalin-2-yl]amino}sulfonyl)phenyl]acetamide 177

4-chloro-N-[3-(2,3-dihydro-1,4-benzodioxin- 6-ylamino)quinoxalin-2-yl]benzenesulfonamide 178

4-chloro-N-[3-[(3,4- dimethylphenyl)amino]quinoxalin-2-yl}benzenesulfonamide 179

N-(3-{[2,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-nitrobenzenesulfonamide 180

4-bromo-N-{3-[(3,4- dimethylphenyl)amino]quinoxalin-2-yl}benzenesulfonamide 181

N-[3-(2,3-dihydro-1,4-benzodioxin-6-ylamino)quinoxalin-2-yl]benzenesulfonamide 182

N-[3-(1,3-benzodioxol-5- ylamino)quinoxalin-2-yl]benzenesulfonamide 183

5-{[3-({[4- (acetylamino)phenyl]sulfonyl}amino)quinoxalin-2-yl]amino}-2-hydroxybenzoic acid 184

N-(3-{[2,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-4-chlorobenzenesulfonamide 185

N-(3-{[2,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-4-methylbenzenesulfonamide 186

N-{3-[(2,4- dichlorophenyl)amino]quinoxalin-2-yl}-4-methylbenzenesulfonamide 187

N-{3-[(2,4-difluorophenyl)amino]quinoxalin- 2-yl}benzenesulfonamide 188

4-bromo-N-{3-[(3- fluorophenyl)amino]quinoxalin-2- yl}benzenesulfonamide189

4-{[3-({[4- (acetylamino)phenyl]sulfonyl}amino)quinoxalin-2-yl]amino}benzoic acid 190

N-{3-[(2-fluorophenyl)amino]quinoxalin-2- yl}-4-methylbenzenesulfonamide191

N-[3-(2,3-dihydro-1,4-benzodioxin-6- ylamino)quinoxalin-2-yl]-4-methylbenzenesulfonamide 192

N-{3-[(3,4- dimethylphenyl)amino]quinoxalin-2- yl}benzenesulfonamide 193

4-methyl-N-(3-{[3- (trifluoromethyl)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide 194

5-[(3-{[(4- chlorophenyl)sulfonyl]amino}quinoxalin-2-yl)amino]-2-hydroxybenzoic acid 195

3-nitro-N-{3-[(1-oxo-1,3-dihydro-2- benzofuran-5-yl)amino]quinoxalin-2-yl}benzenesulfonamide 196

N-{4-[({3-[(2-bromo-4- methylphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]phenyl}acetamide 197

N-{3-[(2-fluorophenyl)amino]quinoxalin-2- yl}-4-nitrobenzenesulfonamide198

N-{3-[(2-methyl-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl)amino]quinoxalin-2-yl}-3- nitrobenzenesulfonamide 199

4-chloro-N-{3-[(1-oxo-1,3-dihydro-2- benzofuran-5-yl)amino]quinoxalin-2-yl}benzenesulfonamide 200

N-{3-[(1-oxo-1,3-dihydro-2-benzofuran-5- yl)amino]quinoxalin-2-yl}benzenesulfonamide 201

N-{3-[(2-fluorophenyl)amino]quinoxalin-2- yl}-3-nitrobenzenesulfonamide202

N-[2-(butyloxy)-2-hydroxyethyl]-4-({3-[(phenylsulfonyl)amino]quinoxalin-2- yl}amino)benzamide 203

3-nitro-N-(3-{[4- (phenylamino)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide 204

4-bromo-N-{3-[(4- fluorophenyl)amino]quinoxalin-2- yl}benzenesulfonamide205

N-(4-{[(3-morpholin-4-ylquinoxalin-2- yl)amino]sulfonyl}phenyl)acetamide206

4-methyl-N-[3-({2- [(trifluoromethyl)thio]phenyl}amino)quinoxalin-2-yl]benzenesulfonamide 207

N-[4-({3-[2-(methyloxy)phenyl]-2,3-dihydro-1H-imidazo[4,5-b]quinoxalin-1- yl}sulfonyl)phenyl]acetamide 208

4-(3-{[4-(acetylamino)phenyl]sulfonyl}-2,3-dihydro-1H-imidazo[4,5-b]quinoxalin-1- yl)benzoic acid 209

1-naphthalen-2-yl-3-[(3- nitrophenyl)sulfonyl]-2,3-dihydro-1H-imidazo[4,5-b]quinoxaline 210

N-[4-({3-[4-(methyloxy)phenyl]-2,3-dihydro-1H-imidazo[4,5-b]quinoxalin-1- yl}sulfonyl)phenyl]acetamide 211

1-(3-methylphenyl)-3-[(4- methylphenyl)sulfonyl]-2,3-dihydro-1H-imidazo[4,5-b]quinoxaline 212

N-(4-{[3-(4-methylphenyl)-2,3-dihydro-1H- imidazo[4,5-b]quinoxalin-1-yl]sulfonyl}phenyl)acetamide 213

N-{4-[(3-phenyl-2,3-dihydro-1H- imidazo[4,5-b]quinoxalin-1-yl)sulfonyl]phenyl}acetamide 214

N-(4-{[3-(3-methylphenyl)-2,3-dihydro-1H- imidazo[4,5-b]quinoxalin-1-yl]sulfonyl}phenyl)acetamide 215

1-[4-(methyloxy)phenyl]-3-[(4- methylphenyl)sulfonyl]-2,3-dihydro-1H-imidazo[4,5-b]quinoxaline 216

N-(4-{[3-(2-methylphenyl)-2,3-dihydro-1H- imidazo[4,5-b]quinoxalin-1-yl]sulfonyl}phenyl)acetamide 217

1-(3-methylphenyl)-3-[(3- nitrophenyl)sulfonyl]-2,3-dihydro-1H-imidazo[4,5-b]quinoxaline 218

1-(4-methylphenyl)-3-[(3- nitrophenyl)sulfonyl]-2,3-dihydro-1H-imidazo[4,5-b]quinoxaline 219

N-{3-[(4-methylphenyl)amino]quinoxalin-2-yl}-3-(1H-tetrazol-1-yl)benzenesulfonamide 220

N-(3-{[2- (ethyloxy)phenyl]amino}quinoxalin-2-yl)-4-methylbenzenesulfonamide 221

N-{4-[({3-[(4-ethylphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]phenyl}acetamide 222

4-bromo-N-(3-{[3- (methyloxy)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide 223

N-(4-{[(3-{[4- (ethyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)acetamide 224

N-{4-[({3-[(2-ethylphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]phenyl}acetamide 225

N-(4-{[(3-{[3- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)acetamide 226

N-(4-{[(3-{[2- (ethyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)acetamide 227

N-{3-[(4-nitrophenyl)amino]quinoxalin-2- yl}benzenesulfonamide 228

4-(ethyloxy)-N-(3-{[4- (methyloxy)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide 229

N-(4-{[(3-piperidin-1-ylquinoxalin-2- yl)amino}sulfonyl}phenyl)acetamide230

N-cyano-N-(3-piperidin-1-ylquinoxalin-2- yl)benzenesulfonamide 231

methyl N-acetyl-N-[4-({3- [(phenylsulfonyl)amino]quinoxalin-2-yl}amino)phenyl]-beta-alaninate 232

methyl N-acetyl-N-{4-[(3-{[(4- chlorophenyl)sulfonyl]amino}quinoxalin-2-yl)amino]phenyl}-beta-alaninate 233

N-{3-[(3-chloro-5- methylphenyl)amino]quinoxalin-2-yl}-4-methylbenzenesulfonamide 234

N-{3-[(3-acetylphenyl)amino]quinoxalin-2- yl}-3-nitrobenzenesulfonamide235

N-[4-(methyloxy)phenyl]-4-({3- [(phenylsulfonyl)amino]quinoxalin-2-yl}amino)benzamide 236

4-{[3-({[4- (acetylamino)phenyl]sulfonyl}amino)quinoxalin-2-yl]amino}-N-[4- (methyloxy)phenyl]benzamide 237

2-hydroxy-5-({3- [(phenylsulfonyl)amino]quinoxalin-2- yl}amino)benzoicacid 238

N-[3-(2,3-dihydro-1,4-benzodioxin-6- ylamino)quinoxalin-2-yl]-3-nitrobenzenesulfonamide 239

N-[4-(methyloxy)phenyl]-4-[(3-{[(4-nitrophenyl)sulfonyl]amino}quinoxalin-2- yl)amino]benzamide 240

4-chloro-N-{3-[(2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)amino]quinoxalin-2- yl}benzenesulfonamide 241

4-methyl-N-{3- [methyl(phenylmethyl)amino]quinoxalin-2-yl}benzenesulfonamide 242

N-[3-(3,4-dihydroisoquinolin-2(1H)- yl)quinoxalin-2-yl]-2-methylbenzenesulfonamide 243

N-[4-({[3-(2,1,3-benzothiadiazol-5- ylamino)quinoxalin-2-yl]amino}sulfonyl)phenyl]acetamide 244

4-bromo-N-{3-[(4-phenylquinolin-8- yl)amino]quinoxalin-2-yl}benzenesulfonamide 245

4-methyl-N-{3-[(4-phenylquinolin-8- yl)amino]quinoxalin-2-yl}benzenesulfonamide 246

1-[(4-chlorophenyl)sulfonyl]-3-[4-(pyrrolidin-1-ylsulfonyl)phenyl]-2,3-dihydro-1H-imidazo[4,5-b]quinoxaline 247

1-(4-morpholin-4-ylphenyl)-3- (phenylsulfonyl)-2,3-dihydro-1H-imidazo[4,5-b]quinoxaline 248

methyl 4,5-dimethyl-2-({3- [(phenylsulfonyl)amino]quinoxalin-2-yl}amino)thiophene-3-carboxylate 249

ethyl 6-methyl-2-[(3-{[(2- methylphenyl)sulfonyl]amino}quinoxalin-2-yl)amino]-4,5,6,7-tetrahydro-1- benzothiophene-3-carboxylate 250

ethyl 2-{[3-({[4- (acetylamino)phenyl]sulfonyl}amino)quinoxalin-2-yl]amino}-6-phenyl-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate 251

ethyl 6-methyl-2-[(3-{[(4- methylphenyl)sulfonyl]amino}quinoxalin-2-yl)amino]-4,5,6,7-tetrahydro-1- benzothiophene-3-carboxylate 252

propyl 4-[(3-{[(4- chlorophenyl)sulfonyl]amino}quinoxalin-2-yl)amino]benzoate 253

N-{3-[(4-butylphenyl)amino]quinoxalin-2- yl}-4-chlorobenzenesulfonamide254

N-{3-[(2-chlorophenyl)amino]quinoxalin-2- yl}-4-methylbenzenesulfonamide255

N-{3-[(2,3- dimethylphenyl)amino]quinoxalin-2-yl}-4-methylbenzenesulfonamide 256

N-{3-[(3,4- dimethylphenyl)amino]quinoxalin-2-yl}-3-nitrobenzenesulfonamide 257

N-{4-[({3-[(2,3- dimethylphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]phenyl}acetamide 258

4-chloro-N-{3-[(2,3- dimethylphenyl)amino]quinoxalin-2-yl}benzenesulfonamide 259

3-nitro-N-(3-{[3,4,5- tris(methyloxy)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide 260

4-chloro-N-{3-[(2,4- dichlorophenyl)amino]quinoxalin-2-yl}benzenesulfonamide 261

N-{3-[(2,3- dimethylphenyl)amino]quinoxalin-2-yl}-3-nitrobenzenesulfonamide 262

N-{4-[({3-[(3,4- dimethylphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]phenyl}acetamide 263

ethyl 2-[(3-{[(4- chlorophenyl)sulfonyl]amino}quinoxalin-2-yl)amino]-5,6-dihydro-4H- cyclopenta[b]thiophene-3-carboxylate 264

4-chloro-N-(3-{[4-chloro-3-(morpholin-4-ylsulfonyl)phenyl]amino}quinoxalin-2- yl)benzenesulfonamide 265

ethyl 2-[(3-{[(2- methylphenyl)sulfonyl]amino}quinoxalin-2-yl)amino]-4,5,6,7-tetrahydro-1- benzothiophene-3-carboxylate 266

4-bromo-N-{3-[(2,4- dichlorophenyl)amino]quinoxalin-2-yl}benzenesulfonamide 267

ethyl 5-ethyl-2-[(3-{[(3- nitrophenyl)sulfonyl]amino}quinoxalin-2-yl)amino]thiophene-3-carboxylate 268

N-(3-{[3-(morpholin-4- ylsulfonyl)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide 269

ethyl 2-[(3-{[(4- bromophenyl)sulfonyl]amino}quinoxalin-2-yl)amino]-4,5,6,7-tetrahydro-1- benzothiophene-3-carboxylate 270

4-methyl-N-(3-{[3-(piperidin-1- ylsulfonyl)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide 271

4-chloro-N-(3-{[4-(morpholin-2- ylsulfonyl)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide 272

4-chloro-N-(3-{[3-(morpholin-2- ylsulfonyl)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide 273

4-methyl-N-[3-(quinolin-6- ylamino)quinoxalin-2-yl]benzenesulfonamide274

N-(3-{[3-(piperidin-1- ylsulfonyl)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide 275

N-(3-{[4- (phenylamino)phenyl]amino}quinoxalin-2- yl)benzenesulfonamide276

N-(3-{[2,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-4-bromobenzenesulfonamide 277

ethyl 2-[(3-{[(3- nitrophenyl)sulfonyl]amino}quinoxalin-2-yl)amino]-5,6-dihydro-4H- cyclopenta[b]thiophene-3-carboxylate 278

N-{3-[(4′-nitrobiphenyl-4- yl)amino]quinoxalin-2- yl}benzenesulfonamide279

ethyl 2-[(3-{[(3- nitrophenyl)sulfonyl]amino}quinoxalin-2-yl)amino]-4,5,6,7-tetrahydro-1- benzothiophene-3-carboxylate 280

N-(3-{[4-chloro-3-(morpholin-4- ylsulfonyl)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide 281

ethyl 5-ethyl-2-({3- [(phenylsulfonyl)amino]quinoxalin-2-yl}amino)thiophene-3-carboxylate 282

N-[4-({[3-(quinolin-6-ylamino)quinoxalin-2-yl]amino}sulfonyl)phenyl]acetamide 283

ethyl 2-[(3-{[(2- methylphenyl)sulfonyl]amino}quinoxalin-2-yl)amino]-5,6-dihydro-4H- cyclopenta[b]thiophene-3-carboxylate 284

3,4-dichloro-N-[3-(naphthalen-1-ylamino)quinoxalin-2-yl]benzenesulfonamide 285

ethyl 2-{[3-({[4-(acetylamino)-3,5-dibromophenyl]sulfonyl}amino)quinoxalin-2-yl]amino}-4,5,6,7-tetrahydro-1- benzothiophene-3-carboxylate 286

ethyl 2-[(3-{[(2-chloro-5- nitrophenyl)sulfonyl]amino}quinoxalin-2-yl)amino]-4,5,6,7-tetrahydro-1- benzothiophene-3-carboxylate 287

N-{3-[(3-fluorophenyl)amino]quinoxalin-2- yl}benzenesulfonamide 288

N-(3-{[4-(morpholin-4- ylsulfonyl)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide 289

ethyl 2-{[3-({[4- (acetylamino)phenyl]sulfonyl}amino)quinoxalin-2-yl]amino}-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate 290

ethyl 2-[(3-{[(4- chlorophenyl)sulfonyl]amino}quinoxalin-2-yl)amino]-5-ethylthiophene-3-carboxylate 291

N,N-diethyl-4-[(3-{[(4- methylphenyl)sulfonyl]amino}quinoxalin-2-yl)amino]benzenesulfonamide 292

ethyl 2-{[3-({[4- (acetylamino)phenyl]sulfonyl}amino)quinoxalin-2-yl]amino}-5-ethylthiophene-3- carboxylate 293

N-[3-(1,3-benzodioxol-5- ylamino)quinoxalin-2-yl]-3-nitrobenzenesulfonamide 294

ethyl 2-[(3-{[(4- chlorophenyl)sulfonyl]amino}quinoxalin-2-yl)amino]-4,5,6,7-tetrahydro-1- benzothiophene-3-carboxylate 295

ethyl 2-({3- [(phenylsulfonyl)amino]quinoxalin-2-yl}amino)-4,5,6,7-tetrahydro-1- benzothiophene-3-carboxylate 296

N-[4-(methyloxy)phenyl]-4-[(3-{[(3-nitrophenyl)sulfonyl]amino}quinoxalin-2- yl)amino]benzamide 297

N-[3-({4-[(4- aminophenyl)oxy]phenyl}amino)quinoxalin-2-yl]-4-chlorobenzenesulfonamide 298

N-[4-({[3-({4-[(4- aminophenyl)oxy]phenyl}amino)quinoxalin-2-yl]amino}sulfonyl)phenyl]acetamide 299

(2E)-3-{3-[(3-{[(4- methylphenyl)sulfonyl]amino}quinoxalin-2-yl)amino]phenyl}prop-2-enoic acid 300

N-{3-[(9-ethyl-9H-carbazol-3- yl)amino]quinoxalin-2-yl}-3-nitrobenzenesulfonamide 301

N-[3-({4-[(4- aminophenyl)oxy]phenyl}amino)quinoxalin-2-yl]benzenesulfonamide 302

4-[(3-{[(4- chlorophenyl)sulfonyl]amino}quinoxalin-2- yl)amino]-N-[4-(methyloxy)phenyl]benzamide 303

4-bromo-N-{3-[(9-ethyl-9H-carbazol-3- yl)amino]quinoxalin-2-yl}benzenesulfonamide 304

N-{3-[(9-ethyl-9H-carbazol-3- yl)amino]quinoxalin-2-yl}benzenesulfonamide 305

N-{3-[(2-iodophenyl)amino]quinoxalin-2- yl}benzenesulfonamide 306

N-{3-[(1-phenylethyl)amino]quinoxalin-2- yl}benzenesulfonamide 307

4-bromo-N-{3-[(4- bromophenyl)amino]quinoxalin-2- yl}benzenesulfonamide308

4-bromo-N-{3-[(4- chlorophenyl)amino]quinoxalin-2- yl}benzenesulfonamide309

4-bromo-N-[3-(naphthalen-2- ylamino)quinoxalin-2-yl]benzenesulfonamide310

N-{3-[(2,3-dimethylphenyl)amino]-6- methylquinoxalin-2-yl}-4-methylbenzenesulfonamide 311

4-chloro-N-{3-[(2- iodophenyl)amino]quinoxalin-2- yl}benzenesulfonamide312

N-(3-{[4- (octyloxy)phenyl]amino}quinoxalin-2- yl)benzenesulfonamide 313

N-[3-(2,1,3-benzothiadiazol-5- ylamino)quinoxalin-2-yl]-3-nitrobenzenesulfonamide 314

N-{3-[(2-bromo-4- methylphenyl)amino]quinoxalin-2- yl}benzenesulfonamide315

N-[3-({4-[(3- aminophenyl)sulfonyl]phenyl}amino) quinoxalin-2-yl]-4-chlorobenzenesulfonamide 316

N-[3-({2- [(difluoromethyl)oxy]phenyl}amino)quinoxalin-2-yl]-3-nitrobenzenesulfonamide 317

8-[(3-{[(4- methylphenyl)sulfonyl]amino}quinoxalin-2-yl)amino]quinoline-2-carboxylic acid 318

ethyl 3,3,3-trifluoro-2-hydroxy-2-{4-[(3-{[(3-nitrophenyl)sulfonyl]amino}quinoxalin- 2-yl)amino]phenyl}propanoate319

N-[3-(quinolin-6-ylamino)quinoxalin-2- yl]benzenesulfonamide 320

4-{[3-({[4- (acetylamino)phenyl]sulfonyl}amino)quinoxalin-2-yl]amino}phenyl thiocyanate 321

1-[3-({[4- (acetylamino)phenyl]sulfonyl}amino)quinoxalin-2-yl]-4-methylpyridinium 322

N-{3-[(2-chlorophenyl)amino]quinoxalin-2- yl}-3-nitrobenzenesulfonamide323

4-methyl-N-[3-(phenylamino)quinoxalin-2- yl]benzenesulfonamide 324

4-methyl-N-{3-[(2- methylphenyl)amino]quinoxalin-2-yl}benzenesulfonamide 325

4-methyl-N-{3-[(4- methylphenyl)amino]quinoxalin-2-yl}benzenesulfonamide 326

N-{3-[(4-chlorophenyl)amino]quinoxalin-2- yl}-4-methylbenzenesulfonamide327

4-methyl-N-[3-(naphthalen-2- ylamino)quinoxalin-2-yl]benzenesulfonamide328

N-{4-[({3-[(4- bromophenyl)amino]quinoxalin-2-yl}amino)sulfonyl]phenyl}acetamide 329

N-{4-[({3-[(2- methylphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]phenyl}acetamide 330

N-{3-[bis(phenylmethyl)amino]quinoxalin-2- yl}benzenesulfonamide 331

N-(3-piperidin-1-ylquinoxalin-2- yl)benzenesulfonamide 332

4-[(3-{[(4- methylphenyl)sulfonyl]amino}quinoxalin-2- yl)amino]benzoicacid 333

2-hydroxy-4-[(3-{[(4- methylphenyl)sulfonyl]amino}quinoxalin-2-yl)amino]benzoic acid 334

4-bromo-N-(3-{[2- (methyloxy)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide 335

4-methyl-N-(3-piperidin-1-ylquinoxalin-2- yl)benzenesulfonamide 336

N-{3-[(3-hydroxyphenyl)amino]quinoxalin- 2-yl}benzenesulfonamide 337

N-[3-(naphthalen-1-ylamino)quinoxalin-2- yl]benzenesulfonamide 338

3-methyl-1-(3-{[(4- methylphenyl)sulfonyl]amino}quinoxalin-2-yl)pyridinium 339

N-(3-{[3-{[(4- chlorophenyl)sulfonyl]amino}-7- (methyloxy)quinoxalin-2-yl]amino}phenyl)acetamide 340

N-{3-[(3-{[(4- chlorophenyl)sulfonyl]amino}quinoxalin-2-yl)amino]phenyl}acetamide 341

N-{3-[(4-bromophenyl)amino]quinoxalin-2- yl}-4-chlorobenzenesulfonamide342

N-{3-[(2,4-dimethylphenyl)amino]-6- methylquinoxalin-2-yl}-4-methylbenzenesulfonamide 343

N-{3-[(3,4- dimethylphenyl)amino]quinoxalin-2-yl}-4-methylbenzenesulfonamide 344

N-{3-[(2,5-dimethylphenyl)amino]-6- methylquinoxalin-2-yl}-4-methylbenzenesulfonamide 345

ethyl 4-[(3-{[(4- chlorophenyl)sulfonyl]amino}quinoxalin-2-yl)amino]benzoate 346

4-chloro-N-{3-[(4- ethylphenyl)amino]quinoxalin-2- yl}benzenesulfonamide347

4-chloro-N-(6-methyl-3-{[4- (methyloxy)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide 348

4-chloro-N-{3-[(4-chlorophenyl)amino]-6-methylquinoxalin-2-yl}benzenesulfonamide 349

N-(3-{[4-chloro-2,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide 350

N-[3-({2-[2,5- bis(methyloxy)phenyl]ethyl}amino)quinoxalin-2-yl]benzenesulfonamide 351

N-(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide 352

N-(3-{[3,4,5- tris(methyloxy)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide 353

N-[3-({3- [(phenylmethyl)oxy]phenyl}amino)quinoxalin-2-yl]benzenesulfonamide 354

N-(3-{[3- (phenyloxy)phenyl]amino}quinoxalin-2- yl)benzenesulfonamide355

N-[3-(piperidin-1-ylamino)quinoxalin-2- yl]benzenesulfonamide 356

N-[3-(4-phenylpiperazin-1-yl)quinoxalin-2- yl]benzenesulfonamide 357

N-{3-[4-(phenylmethyl)piperidin-1- yl]quinoxalin-2-yl}benzenesulfonamide358

N-{3-[(4-morpholin-4- ylphenyl)amino]quinoxalin-2- yl}benzenesulfonamide359

N-(3-{[3-(methyloxy)-5- (trifluoromethyl)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide 360

N-(3-{[2,5- bis(ethyloxy)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide 361

N-(3-morpholin-4-ylquinoxalin-2- yl)benzenesulfonamide 362

N-(3-{[2,5- bis(methyloxy)phenyl]amino}pyrazin-2-yl)-4-chlorobenzenesulfonamide 363

N-(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-4-methylbenzenesulfonamide 364

N-(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-nitrobenzenesulfonamide 365

N-(3-azidoquinoxalin-2- yl)benzenesulfonamide 366

N-[3-({[2,5- bis(methyloxy)phenyl]methyl}amino)quinoxalin-2-yl]benzenesulfonamide 367

N-(3-{[2-methyl-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide 368

N-[3-(dimethylamino)quinoxalin-2- yl]benzenesulfonamide 369

N-(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)naphthalene-2-sulfonamide 370

4-(3-Benzensulfonylamino-quinoxalin-2-yl)- piperazine-1-carboxylic acidtert-butyl ester 371

N-[3-(2-Chloro-5-methoxy-phenylamino)-quinoxalin-2-yl]-benzenesulfonamide 372

3-amino-N-(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide 373

N-(3-piperazin-1-ylquinoxalin-2- yl)benzenesulfonamide 374

N-(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-4-chlorobenzenesulfonamide 375

N-(3-{4-[(9-oxo-9H-fluoren-1- yl)carbonyl]piperazin-1-yl}quinoxalin-2-yl)benzenesulfonamide 376

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)acetamide 377

N-(3-{[4-chloro-3- (methyloxy)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide 378

N-(3-{[4-fluoro-3- (methyloxy)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide 379

N-(3-{[2′-(methyloxy)biphenyl-4- yl]amino}quinoxalin-2-yl)benzenesulfonamide 380

N-(3-{[5-methyl-2- (methyloxy)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide 381

3-amino-N-(3-{[2,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide 382

N-(3-{[2,5-bis(methyloxy)phenyl]amino}- 6,7-dimethylquinoxalin-2-yl)benzenesulfonamide 383

N-(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-4-bromobenzenesulfonamide 384

N-(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)-3-nitrobenzenesulfonamide 385

N-(3-{[5-chloro-2- (methyloxy)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide 386

N-(3-{[2-(methyloxy)-5- (trifluoromethyl)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide 387

N-(3-{[2-(methyloxy)biphenyl-4- yl]amino}quinoxalin-2-yl)benzenesulfonamide 388

3-amino-N-(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide 389

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-,N-2- dimethylglycinamide 390

N-(3-{[2,5-bis(methyloxy)phenyl]amino}-7-methylquinoxalin-2-yl)benzenesulfonamide 391

N-(3-{[2,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-4-(methyloxy)benzenesulfonamide 392

N-(3-{[2,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-bromobenzenesulfonamide 393

N-(3-{[2,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-fluorobenzenesulfonamide 394

N-(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-fluorobenzenesulfonamide 395

N-(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-4-(methyloxy)benzenesulfonamide 396

N-(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-bromobenzenesulfonamide 397

N-(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-1- methylpiperidine-4-carboxamide 398

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-3-piperidin-1- ylpropanamide 399

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-4- (dimethylamino)butanamide 400

N-(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-(hydroxyamino)benzenesulfonamide 401

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-morpholin-4- ylacetamide 402

N-(3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-4-methylphenyl)-N-2- methylglycinamide 403

N-(3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-4-methylphenyl)-L- alaninamide 404

N-(3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-4-methylphenyl)-2- methylalaninamide 405

N-(3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-4-methylphenyl)-N-2-,N- 2-dimethylglycinamide 406

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-D-alaninamide 407

N-(3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2- methylglycinamide 408

N-(3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-4-methylphenyl)-D- alaninamide 409

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2- methylglycinamide 410

N-(3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-L-alaninamide 411

N-(3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-D-alaninamide 412

N-(3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2- methylalaninamide 413

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2- methylalaninamide 414

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-4-methylphenyl)-N-2-,N- 2-dimethylglycinamide 415

N-(3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-[2- (dimethylamino)ethyl]-N-2-methylglycinamide 416

(2S)-2-amino-N-(3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)butanamide 417

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-[2- (dimethylamino)ethyl]-N-2-methylglycinamide 418

N-(3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino}sulfonyl}phenyl)-N-2-,N-2- dimethylglycinamide 419

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-methyl-L- alaninamide 420

N-(3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)glycinamide 421

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)glycinamide 422

N-(2-chloro-5-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2- methylglycinamide 423

2-(dimethylamino)-N-(3-(N-(3-(3-(2- (dimethylamino)acetamido)-5-methoxyphenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)acetamide 424

N-(3-{[(3-{[2-acetyl-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-,N-2- dimethylglycinamide 425

N-(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)-3-(formylamino)benzenesulfonamide 426

N-(3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2- ethylglycinamide 427

N-(5-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-2- methylphenyl)glycinamide 428

2-azetidin-1-yl-N-(3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2- yl)amino]sulfonyl}phenyl)acetamide429

N-(3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-L-prolinamide 430

N-(3-{[(3-{[2-bromo-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2- methylglycinamide 431

N-2-,N-2-dimethyl-N-(3-{[(3-{[6-(methyloxy)quinolin-8-yl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)glycinamide 432

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-L-alaninamide 433

N-(3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-methyl-D- alaninamide 434

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-L-prolinamide 435

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-D-serinamide 436

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)azetidine-3- carboxamide 437

N-(3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-,2- dimethylalaninamide 438

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-methyl-D- alaninamide 439

N-(3-{[(3-{[2-bromo-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino}sulfonyl}phenyl)-N-2-,N-2- dimethylglycinamide 440

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino}sulfonyl}phenyl)-N-2- propylglycinamide 441

N-(3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-methyl-L- alaninamide 442

N-(5-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-2-methylphenyl)-beta- alaninamide 443

N-(3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)piperidine-3- carboxamide 444

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(4-methyl-1,4- diazepan-1-yl)acetamide 445

(2S)-2-amino-N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)butanamide 446

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-(2- hydroxypropyl)glycinamide 447

N-(3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-(2- fluoroethyl)glycinamide 448

3-amino-N-(2-{[3,5- bis(methyloxy)phenyl]amino}pyrido[2,3-b]pyrazin-3-yl)benzenesulfonamide 449

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-[(2- methylpropyl)oxy]glycinamide 450

1-amino-N-(3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl) cyclopropanecarboxamide 451

N-(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-(formylamino)benzenesulfonamide 452

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2- (cyclopropylmethyl)glycinamide 453

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-D-prolinamide 454

N-(3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-[3- (dimethylamino)azetidin-1-yl]acetamide455

N-(3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-D-prolinamide 456

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)piperidine-2- carboxamide 457

N-(3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)morpholine-4- carboxamide 458

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-pyrrolidin-1- ylacetamide 459

N-(3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-6-,N-6- dimethyl-L-lysinamide 460

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-ethyl-N-2- methylglycinamide 461

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(1H-imidazol- 4-yl)acetamide 462

1-amino-N-(3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl) cyclopentanecarboxamide 463

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-(2- methylpropyl)glycinamide 464

N-(3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-ethyl-N-2- methylglycinamide 465

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-1-(1H-imidazol-4-ylmethyl)azetidine-3-carboxamide 466

N-(5-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-2-methylphenyl)-N-2-,N- 2-dimethylglycinamide 467

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-1-ethylazetidine- 3-carboxamide 468

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-methyl-N-2-(1-methylpyrrolidin-3-yl)glycinamide 469

N-(3-{[(2-{[3,5- bis(methyloxy)phenyl]amino}pyrido[2,3-b]pyrazin-3-yl)amino]sulfonyl}phenyl)-N-2- [2-(dimethylamino)ethyl]-N-2-methylglycinamide 470

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-[(3S)-3- hydroxypyrrolidin-1-yl]acetamide471

1-amino-N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl) cyclobutanecarboxamide 472

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2- butylglycinamide 473

N-(3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(3-piperidin-1- ylazetidin-1-yl)acetamide474

3-[(aminocarbonyl)amino]-N-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2- yl)benzenesulfonamide 475

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-1- hydroxycyclopropanecarboxamide 476

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(2,2- dimethylhydrazino)acetamide 477

N-(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2- yl)-3-[({[2-(dimethylamino)ethyl]amino}carbonyl) amino]benzenesulfonamide 478

N-(3-{[(3-{[3-fluoro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2- methylglycinamide 479

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2- hydroxyacetamide 480

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)pyridazine-4- carboxamide 481

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-(1- methylethyl)glycinamide 482

1-amino-N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl) cyclopentanecarboxamide 483

1-amino-N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl) cyclopropanecarboxamide 484

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-[3- (dimethylamino)pyrrolidin-1-yl]acetamide485

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-[2- (dimethylamino)ethyl]glycinamide 486

2-(dimethylamino)ethyl(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)carbamate 487

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-1- (cyclopropylmethyl)azetidine-3-carboxamide488

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-(1,1- dimethylethyl)glycinamide 489

N-2-methyl-N-(3-{[(3-{[3- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)glycinamide 490

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-1H-imidazole-2- carboxamide 491

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)isoxazole-5- carboxamide 492

N-(3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-(2,2,2- trifluoroethyl)glycinamide 493

3-amino-N-(3-{[2-methyl-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide 494

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-3- oxocyclopentanecarboxamide 495

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-6- hydroxypyridine-2-carboxamide 496

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-(3-fluoro-4- hydroxyphenyl)glycinamide 497

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-1-(furan-2- ylmethyl)azetidine-3-carboxamide498

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)pyrimidine-5- carboxamide 499

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-1H-pyrrole-2- carboxamide 500

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-methyl-N-2- (1-methylethyl)glycinamide 501

N-(3-{[(3-{[3-fluoro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-,N-2- dimethylglycinamide 502

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-1H-imidazole-4- carboxamide 503

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-,N-2- diethylglycinamide 504

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(3- methylisoxazol-5-yl)acetamide 505

N-2-,N-2-dimethyl-N-(3-{[(3-{[2-methyl-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)glycinamide 506

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-[(3- hydroxyphenyl)methyl]glycinamide 507

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-1-methyl-1H- pyrrole-2-carboxamide 508

4-amino-N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)tetrahydro-2H- pyran-4-carboxamide 509

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-[4- (methylamino)piperidin-1-yl]acetamide510

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-piperidin-1- ylacetamide 511

N-(4-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-,N-2- dimethylglycinamide 512

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-1-methyl-L- prolinamide 513

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)thiophene-3- carboxamide 514

3-amino-N-{3-[(2-chloro-5- hydroxyphenyl)amino]quinoxalin-2-yl}benzenesulfonamide 515

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-1- (cyclopropylcarbonyl)azetidine-3-carboxamide 516

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(4- methylpiperazin-2-yl)acetamide 517

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenylmethyl)azetidine-3- carboxamide 518

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-chloropyridine- 3-carboxamide 519

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-pyridin-4- ylacetamide 520

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-methyl-N-2- prop-2-en-1-ylglycinamide 521

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2- (phenylmethyl)glycinamide 522

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2- (methyloxy)acetamide 523

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-1- propanoylazetidine-3-carboxamide 524

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)pyridine-3- carboxamide 525

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-[2- (methyloxy)ethyl]glycinamide 526

1-acetyl-N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)piperidine-4- carboxamide 527

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(2- methylpyrrolidin-1-yl)acetamide 528

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)furan-3- carboxamide 529

N-2-,N-2-dimethyl-N-(3-{[(3-{[3- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)glycinamide 530

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-6-chloropyridine- 3-carboxamide 531

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2- chlorobenzamide 532

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-pyridin-2- ylacetamide 533

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-[3- (dimethylamino)azetidin-1-yl]acetamide534

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-pyridin-3- ylacetamide 535

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(2- chlorophenyl)acetamide 536

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-[3- (dimethylamino)propyl]-N-2-methylglycinamide 537

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-ethyl-N-2-(2- hydroxyethyl)glycinamide 538

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-[2- (phenylmethyl)pyrrolidin-1-yl]acetamide539

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)propanamide 540

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)furan-2- carboxamide 541

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-chloropyridine- 4-carboxamide 542

N-2-acetyl-N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)glycinamide 543

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)butanamide 544

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-4- chlorobenzamide 545

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-4- methylbenzamide 546

1,1-dimethylethyl{2-[(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)amino]-2- oxoethyl}carbamate 547

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-1,3- benzodioxole-5-carboxamide 548

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-({[2-(methyloxy)phenyl]methyl}oxy)glycinamide 549

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)pyridine-4- carboxamide 550

N-(3-{[(3-{[4-fluoro-3- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-,N-2- dimethylglycinamide 551

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-[4-(3,4-dichlorophenyl)piperazin-1-yl]acetamide 552

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-3-pyridin-3- ylpropanamide 553

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)tetrahydrofuran-3- carboxamide 554

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-[(2- methylphenyl)methyl]glycinamide 555

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2- methylbutanamide 556

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(3- fluorophenyl)acetamide 557

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-(1-methyl-1- phenylethyl)glycinamide 558

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2- methylcyclopropanecarboxamide 559

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-methyl-4- (methyloxy)benzamide 560

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-methylpyridine- 3-carboxamide 561

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-4- (methyloxy)benzamide 562

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(4- ethylpiperazin-1-yl)acetamide 563

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)thiophene-2- carboxamide 564

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-3-fluoro-2- methylbenzamide 565

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2- bromothiophene-3-carboxamide 566

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-4- fluorobenzamide 567

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(3- methylpiperidin-1-yl)acetamide 568

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2- methylpropanamide 569

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)pentanamide 570

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2- (ethyloxy)acetamide 571

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-(2- fluorophenyl)glycinamide 572

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-3- (dimethylamino)benzamide 573

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(4- methylpiperidin-1-yl)acetamide 574

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-(2- propylphenyl)glycinamide 575

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)benzamide 576

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)pyrazine-2- carboxamide 577

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-3-fluoro-4- (methyloxy)benzamide 578

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2,2- dimethylbutanamide 579

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-[(4- fluorophenyl)oxy]acetamide 580

1-acetyl-N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)azetidine-3- carboxamide 581

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-(4- methylphenyl)glycinamide 582

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2- phenylglycinamide 583

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(4-prop-2-en-1- ylpiperazin-1-yl)acetamide584

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2- methylbenzamide 585

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-3- (methyloxy)propanamide 586

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-3-methylfuran-2- carboxamide 587

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2,2- dimethylpropanamide 588

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2- [(phenylmethyl)oxy]glycinamide 589

N-(3-[({3-[(2-chloro-5- hydroxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]phenyl}-N-2-,N-2- dimethylglycinamide 590

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-(3- chlorophenyl)glycinamide 591

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl) cyclobutanecarboxamide 592

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-[3- (methyloxy)phenyl]acetamide 593

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-1- methylcyclopropanecarboxamide 594

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-3- fluorobenzamide 595

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-4- (dimethylamino)benzamide 596

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-3,4- dichlorobenzamide 597

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-{[2- (methylthio)phenyl]methyl}glycinamide598

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(2- fluorophenyl)acetamide 599

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-ethyl-N-2-(1- methylethyl)glycinamide 600

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-1,3-thiazole-4- carboxamide 601

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-methyl-N-2- (phenylmethyl)glycinamide 602

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-(2- thienylmethyl)glycinamide 603

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-(pyridin-2- ylmethyl)glycinamide 604

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-3- (methyloxy)benzamide 605

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-[(3-chloro-4-methylphenyl)methyl]glycinamide 606

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2- methylpentanamide 607

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(4- chlorophenyl)acetamide 608

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-3-fluoro-4- methylbenzamide 609

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-[(2- methylphenyl)oxy]acetamide 610

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2- cyclohexylacetamide 611

(1R,2R)-N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2- phenylcyclopropanecarboxamide 612

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-3- chlorobenzamide 613

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-[2- (methyloxy)phenyl]acetamide 614

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-3-[3- (methyloxy)phenyl]propanamide 615

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-(2-fluoro-4- methylphenyl)glycinamide 616

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-[(3- fluorophenyl)methyl]glycinamide 617

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-[4- (methyloxy)phenyl]acetamide 618

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2- phenylacetamide 619

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2,4- dichlorobenzamide 620

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-3- oxocyclohexanecarboxamide 621

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-(3- fluorophenyl)glycinamide 622

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(3- chlorophenyl)acetamide 623

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-(2- phenylpropyl)glycinamide 624

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-[(2,4- dimethylphenyl)methyl]glycinamide625

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(2- methylpiperidin-1-yl)acetamide 626

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-[2- (methyloxy)phenyl]glycinamide 627

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(3,4- dihydyoisoquinolin-2(1H)-yl)acetamide628

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)pent-4-enamide 629

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-(2- methylphenyl)glycinamide 630

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(4- oxopiperidin-1-yl)acetamide 631

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2- fluorobenzamide 632

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-(1- phenylethyl)glycinamide 633

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-fluoro-6- (methyloxy)benzamide 634

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-[2-(1- methylethyl)phenyl]glycinamide 635

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-3-[2- (methyloxy)phenyl]propanamide 636

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-4- methylpentanamide 637

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(2- phenylmorpholin-4-yl)acetamide 638

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-3-[4- (methyloxy)phenyl]propanamide 639

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-cyclopentyl- N-2-prop-2-en-1-ylglycinamide640

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-methyl-N-2- [2-(methyl-N-2-[2-(methyloxy)ethyl]glycinamide 641

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-4-cyclopropyl-4- oxobutanamide 642

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-[3-(1,1- dimethylethyl)phenyl]glycinamide643

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2- (cyclopropylmethyl)-N-2-propylglycinamide644

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(2- oxocyclopentyl)acetamide 645

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-(4- chlorophenyl)glycinamide 646

2-(1,4′-bipiperidin-1′-yl)-N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)acetamide 647

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(4- cyclopentylpiperazin-2-yl)acetamide 648

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(2- methylphenyl)acetamide 649

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-[(5-fluoro-2-methylphenyl)methylphenyl)methyl] glycinamide 650

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-3,3- dimethylbutanamide 651

2-(2-chlorophenylamino)-N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)acetamide 652

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-5-fluoro-2- methylbenzamide 653

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-4-fluoro-3- methylbenzamide 654

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2,3- dichlorobenzamide 655

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2- (phenyloxy)acetamide 656

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-(2,3- dimethylphenyl)glycinamide 657

3-amino-N-(3-{[3,5- bis(methyloxy)phenyl]amino}pyrido[2,3-b]pyrazin-2-yl)benzenesulfonamide 658

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-fluoro-5- methylbenzamide 659

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-{[(4- methylphenyl)methyl]oxy}glycinamide660

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-[(1- methylethyl)piperazin-1-yl]acetamide661

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(4- fluorophenyl)acetamide 662

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-3- methylbutanamide 663

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-4-methyl-2- (methyloxy)benzamide 664

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(4- propylpiperidin-1-yl)acetamide 665

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-[(3- methylphenyl)oxy]acetamide 666

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)tetrahydrofuran-2- carboxamide 667

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-[3- (hydroxymethyl)piperidin-1-yl]acetamide668

1,1-dimethylethyl2-{[(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)amino]carbonyl} piperidine-1-carboxylate 669

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-methyl-N-2-(pyridin-3-ylmethyl)glycinamide 670

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-ethyl-N-2- phenylglycinamide 671

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-{[2- (methyloxy)ethyl]oxy}acetamide 672

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-3- cyclopentylpropanamide 673

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2,5- dichlorobenzamide 674

2-(4-acetylpiperazin-1-yl)-N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)acetamide 675

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-5-fluoro-2- (methyloxy)benzamide 676

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-cyclohexyl- N-2-ethylglycinamide 677

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-5- methylisoxazole-3-carboxamide 678

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-3-methylpyridine- 2-carboxamide 679

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2- (methyloxy)pyridine-3-carboxamide 680

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-3,5- dichlorobenzamide 681

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(1,3- thiazolidin-3-yl)acetamide 682

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(4- formylpiperazin-1-yl)acetamide 683

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(2-pyridin-4- ylpiperidin-1-yl)acetamide 684

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2- (methyloxy)benzamide 685

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-methyl-N-2- (2-methylpropyl)glycinamide686

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(4-formyl-1,4- diazepan-1-yl)acetamide 687

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-1- phenylcyclopropanecarboxamide 688

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(2,6- dimethylmorpholin-4-yl)acetamide 689

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(2- phenylpyrrolidin-1-yl)acetamide 690

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(2,6- dimethylpiperidin-1-yl)acetamide 691

N-{3-[({3-[(4- chlorophenyl)amino]quinoxalin-2-yl}amino)sulfonyl]phenyl}-N-2-,N-2- dimethylglycinamide 692

N-{3-[({3-[(3- fluorophenyl)amino]quinoxalin-2-yl}amino)sulfonyl]phenyl}-N-2-,N-2- dimethylglycinamide 693

N-{3-[({3-[(3- chlorophenyl)amino]quinoxalin-2-yl}amino)sulfonyl]phenyl}-N-2-,N-2- dimethylglycinamide 694

3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-[2-(dimethylamino)-1- methylethyl]benzamide 695

3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-[2- (dimethylamino)ethyl]benzamide 696

5-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-[2- (dimethylamino)ethyl]-2-fluorobenzamide 697

3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-pyrrolidin-3- ylbenzamide 698

3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-[2- (dimethylamino)ethyl]benzamide 699

3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-(2-pyrrolidin-1- ylethyl)benzamide 700

N-(2-aminoethyl)-3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2- yl)amino]sulfonyl}benzamide 701

3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-[2- (dimethylamino)ethyl]-N-methylbenzamide 702

3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-(piperidin-2- ylmethyl)benzamide 703

3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-(1-methylazetidin-3- yl)benzamide 704

3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-(2-piperidin-1- ylethyl)benzamide 705

3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-[2- (diethylamino)ethyl]benzamide 706

3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-[2- (dimethylamino)ethyl]-N-methylbenzamide 707

3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-(1-methylpiperidin-3- yl)benzamide 708

3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-piperidin-3- ylbenzamide 709

3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-[(1-methylpiperidin-2- yl)methyl]benzamide 710

N-{2-[bis(2-hydroxyethyl)amino]ethyl}-3- {[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2- yl)amino]sulfonyl}benzamide 711

3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-(1-ethylpiperidin-3- yl)benzamide 712

3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}benzamide 713

3-[(3-aminopyrrolidin-1-yl)carbonyl]-N-(3- {[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2- yl)benzenesulfonamide 714

5-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-[2- (dimethylamino)ethyl]-2- (methyloxy)benzamide715

N-(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)-3-{[3-(methylamino)pyrrolidin-1- yl]carbonyl}benzenesulfonamide 716

3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}benzoicacid 717

3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-(2-morpholin-4- ylethyl)benzamide 718

3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-[(1-ethylpyrrolidin-2- yl)methyl]benzamide 719

3-[(4-amino-3-oxopyrazolidin-1- yl)carbonyl]-N-(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2- yl)benzenesulfonamide 720

3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-methylbenzamide 721

3-[(3-aminoazetidin-1-yl)carbonyl]-N-(3-{[2- chloro-5-(methyloxy)phenyl]amino}quinoxalin-2- yl)benzenesulfonamide 722

3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-(pyridin-3- ylmethyl)benzamide 723

3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-(pyridin-2- ylmethyl)benzamide 724

3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-(2- hydroxyethyl)benzamide 725

3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-(3-oxopyrazolidin-4- yl)benzamide 726

3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-[2-(1H-imidazol-4- yl)ethyl]benzamide 727

N-(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)-3-{[3-(dimethylamino)pyrrolidin-1- yl]carbonyl}benzenesulfonamide 728

3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-(pyridin-4- ylmethyl)benzamide 729

3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-methyl-N-(1- methylpyrrolidin-3-yl)benzamide 730

N-(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)-3-{[3-(diethylamino)pyrrolidin-1- yl]carbonyl}benzenesulfonamide 731

3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-1H-pyrrol-1- ylbenzamide 732

3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-(3-pyrrolidin-1- ylpropyl)benzamide 733

3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-(2-cyanoethyl)-N- methylbenzamide 734

3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-[2- (methyloxy)ethyl]benzamide 735

3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-(2-cyanoethyl)-N- ethylbenzamide 736

3-[(3-aminopiperidin-1-yl)carbonyl]-N-(3- {[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2- yl)benzenesulfonamide 737

3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}benzoicacid 738

3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-[3- (dimethylamino)propyl]benzamide 739

3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-morpholin-4- ylbenzamide 740

N-(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)- 3-[(2,2-dimethylhydrazino)carbonyl] benzenesulfonamide 741

3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-[3-(1H-imidazol-1- yl)propyl]benzamide 742

3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-[3- (diethylamino)propyl]benzamide 743

3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-(2- cyanoethyl)benzamide 744

methylN-[(3-[(3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)carbonyl]-beta- alaninate 745

3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-[2- (methylthio)ethyl]benzamide 746

3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-[2- (ethylthio)ethyl]benzamide 747

3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-[2- (dimethylamino)ethyl]-N-ethylbenzamide 748

3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-[3-(2-oxopyrrolidin-1- yl)propyl]benzamide 749

3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-(2-pyridin-4- ylethyl)benzamide 750

3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-[3- (ethyloxy)propyl]benzamide 751

3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-(3-morpholin-4- ylpropyl)benzamide 752

3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-[3- (methyloxy)propyl]benzamide 753

3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-[3- (dimethylamino)propyl]-N-methylbenzamide 754

3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-[3- (propyloxy)propyl]benzamide 755

ethylN-[(3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)carbonyl]-beta- alaninate 756

3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-{3-[(1- methylethyl)oxy]propyl}benzamide 757

3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-(1,1-dimethyl-2- piperidin-1-ylethyl)benzamide 758

3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-methyl-N- propylbenzamide 759

3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-piperidin-1- ylbenzamide 760

3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-[1-methyl-2- (methyloxy)ethyl]benzamide 761

3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-(1,1-dimethyl-2- morpholin-4-ylethyl)benzamide 762

N-(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)-3-({2-[(dimethylamino)methyl]piperidin-1- yl}carbonyl)benzenesulfonamide763

N-[3-(butyloxy)propyl]-3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2- yl)amino]sulfonyl}benzamide 764

3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-[4-(diethylamino)-1- methylbutyl]benzamide 765

3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-(1,1-dimethyl-2-oxo-2-piperidin-1-ylethyl)benzamide 766

N-(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)-3-[(4-methylpiperazin-1- yl)carbonyl]benzenesulfonamide 767

N-(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)-3-{[2-(piperidin-1-ylmethyl)piperidin-1- yl]carbonyl}benzenesulfonamide768

N-(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)-6-oxo-1,6-dihydropyridine-3-sulfonamide 769

N-(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-6-oxo-1,6-dihydropyridine-3-sulfonamide 770

3-amino-N-(3-{[6-(methyloxy)quinolin-8- yl]amino}quinoxalin-2-yl)benzenesulfonamide 771

N-(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)thiophene-2-sulfonamide 772

N-(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)-3-cyanobenzenesulfonamide 773

N-(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-(methylamino)benzenesulfonamide 774

N-(2-{[3,5- bis(methyloxy)phenyl]amino}pyrido[2,3-b]pyrazin-3-yl)-3-nitrobenzenesulfonamide 775

N-(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)- 3-(1-{[2-(dimethylamino)ethyl]amino}ethyl) benzenesulfonamide 776

3-amino-N-(3-{[3-(methyloxy)-5- nitrophenyl]amino}quinoxalin-2-yl)benzenesulfonamide 777

3-acetyl-N-(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide 778

3-amino-N-(3-{[3-fluoro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide 779

N-(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)-N′-[2-(dimethylamino)ethyl]benzene-1,3- disulfonamide 780

N-(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)-N′-[3-(dimethylamino)propyl]benzene-1,3- disulfonamide 781

N-(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-6-chloropyridine-3-sulfonamide 782

N-(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)-3-{5-[(dimethylamino)methyl]-1,3,4- oxadiazol-2-yl}benzenesulfonamide783

N-(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2- yl)-6-{[2-(dimethylamino)ethyl]amino}pyridine-3- sulfonamide 784

3-amino-N-(3-{[3-amino-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide 785

N-(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-(dimethylamino)benzenesulfonamide 786

N-(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2- yl)-6-{[2-(dimethylamino)ethyl]oxy}pyridine-3- sulfonamide 787

N-(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-6-(dimethylamino)pyridine-3- sulfonamide 788

N-{3-[({3-[(4- fluorophenyl)amino]quinoxalin-2-yl}amino)sulfonyl]phenyl}-N-2-,N-2- dimethylglycinamide 789

N-(3-{[2-chloro-6-(methyloxy)pyridin-4- yl]amino}quinoxalin-2-yl)-3-nitrobenzenesulfonamide 790

N-(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-4-cyanobenzenesulfonamide 791

N-(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-4-fluorobenzenesulfonamide 792

N-(3-{[3,5- bis(methyloxy)phenyl]amino}amino}quinoxalin-2-yl)-4-fluoro-2- methylbenzenesulfonamide 793

N-(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-2-methylbenzenesulfonamide 794

N-(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-cyanobenzenesulfonamide 795

N-(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-3,5-difluorobenzenesulfonamide 796

N-(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-2-chlorobenzenesulfonamide 797

N-(4-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)acetamide 798

N-(3-{[6-(methyloxy)quinolin-3- yl]amino}quinoxalin-2-yl)-3-nitrobenzenesulfonamide 799

N-(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-(2H-tetrazol-5-yl)benzenesulfonamide 800

N-(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)naphthalene-1-sulfonamide 801

3-nitro-N-[3-(pyridin-4-ylamino)quinoxalin- 2-yl]benzenesulfonamide 802

N-{3-[(2,6-dichloropyridin-4- yl)amino]quinoxalin-2-yl}-3-nitrobenzenesulfonamide 803

N-{3-[(2-chloropyridin-4- yl)amino]quinoxalin-2-yl}-3-nitrobenzenesulfonamide 804

N-(3-{[4,6-bis(methyloxy)pyrimidin-2- yl]amino}quinoxalin-2-yl)-3-nitrobenzenesulfonamide 805

N-(3-{[4-hydroxy-6-(methyloxy)pyrimidin- 2-yl]amino}quinoxalin-2-yl)-3-nitrobenzenesulfonamide 806

N-{[(3-{[(3-{[2-chloro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-4- methylphenyl)amino](dimethylamino)methylidene}-N-methylmethanaminium 807

N-(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-fluorobenzenesulfonamide 808

N-(3-{[2-bromo-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)-3-nitrobenzenesulfonamide 809

N-(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2- yl)-4-[(difluoromethyl)oxy]benzenesulfonamide 810

N-(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-2-(trifluoromethyl)benzenesulfonamide 811

N-(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-chloro-4-fluorobenzenesulfonamide 812

N-(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-4-(trifluoromethyl)benzenesulfonamide 813

N-(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-(methylsulfonyl)benzenesulfonamide 814

N-(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-2,5-dichlorothiophene-3-sulfonamide 815

N-(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-3,5-dichlorobenzenesulfonamide 816

N-(3-{[2-methyl-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)-3-nitrobenzenesulfonamide 817

N-(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2- yl)-4-[(trifluoromethyl)oxy]benzenesulfonamide 818

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-[4- (dimethylamino)piperidin-1-yl]acetamide819

N-(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2- yl)-5-chloro-2-(methyloxy)benzenesulfonamide 820

N-(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-(trifluoromethyl)benzenesulfonamide 821

N-(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-2,5-bis(methyloxy)benzenesulfonamide 822

N-(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-3,5-dimethylisoxazole-4-sulfonamide 823

N-(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2- yl)-5-bromo-2-(methyloxy)benzenesulfonamide 824

N-(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2- yl)-4-fluoro-3-(trifluoromethyl)benzenesulfonamide 825

N-(3-{[3-fluoro-5- (methyloxy)phenyl]amino}quinoxalin-2-yl)-3-nitrobenzenesulfonamide 826

N-(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-fluoro-4-methylbenzenesulfonamide 827

N-(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-chloro-4-methylbenzenesulfonamide 828

N-(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-2,5-dimethylthiophene-3-sulfonamide 829

N-(3-{[3- (methyloxy)phenyl]amino}quinoxalin-2-yl)-3-nitrobenzenesulfonamide 830

N-{3-[(2-chloro-5- hydroxyphenyl)amino]quinoxalin-2-yl}-3-nitrobenzenesulfonamide 831

N-(3-{[(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-4-methyl-3- (methyloxy)benzamide 832

N-(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-1-phenylmethanesulfonamide 833

N-(3-{[3-(methyloxy)-5- nitrophenyl]amino}quinoxalin-2-yl)-3-nitrobenzenesulfonamide 834

N-(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-1-(3-chlorophenyl)methanesulfonamide 835

N-(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-4,5-dichlorothiophene-2-sulfonamide 836

N-(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-5-chloro-1,3-dimethyl-1H-pyrazole-4- sulfonamide 837

N-(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2- yl)-3,5-bis(trifluoromethyl)benzenesulfonamide 838

N-{3-[(3- hydroxyphenyl)amino]quinoxalin-2-yl}-3-nitrobenzenesulfonamide 839

3-nitro-N-[3-({3- [(trifluoromethyl)oxy]phenyl}amino)quinoxalin-2-yl]benzenesulfonamide 840

3-nitro-N-[3-(pyridin-3-ylamino)quinoxalin- 2-yl]benzenesulfonamide 841

N-[3-(morpholin-4-ylamino)quinoxalin-2-yl]- 3-nitrobenzenesulfonamide842

3-[(3-{[(3- nitrophenyl)sulfonyl]amino}quinoxalin-2-yl)amino]phenyldimethylcarbamate 843

N-{3-[(2-chloropyridin-3- yl)amino]quinoxalin-2-yl}-3-nitrobenzenesulfonamide 844

3-nitro-N-[3-(tetrahydro-2H-pyran-4-ylamino)quinoxalin-2-yl]benzenesulfonamide 845

N-{3-[(4-fluorophenyl)amino]quinoxalin-2- yl}benzenesulfonamide 846

N-[3-({3-[(1- methylethyl)oxy]phenyl}amino)quinoxalin-2-yl]-3-nitrobenzenesulfonamide 847

N-{3-[(3-hydroxy-2- methylphenyl)amino]quinoxalin-2-yl}-3-nitrobenzenesulfonamide 848

N-{3-[(2,5-difluorophenyl)amino]quinoxalin-2-yl}-3-nitrobenzenesulfonamide 849

N-[3-({3- [(difluoromethyl)oxy]phenyl}amino)quinoxalin-2-yl]-3-nitrobenzenesulfonamide 850

N-(3-{[2-(methyloxy)pyridin-3- yl]amino}quinoxalin-2-yl)-3-nitrobenzenesulfonamide 851

N-(3-{[3- (ethyloxy)phenyl]amino}quinoxalin-2-yl)-3-nitrobenzenesulfonamide 852

N-{3-[(2,2-difluoro-1,3-benzodioxol-4- yl)amino]quinoxalin-2-yl}-3-nitrobenzenesulfonamide 853

N-{3-[(3-{[(3- nitrophenyl)sulfonyl]amino}quinoxalin-2-yl)amino]phenyl}acetamide 854

N-[3-(4-amino-1H-indol-1-yl)quinoxalin-2- yl]-3-nitrobenzenesulfonamide855

N-[3-(1H-indol-4-ylamino)quinoxalin-2-yl]- 3-nitrobenzenesulfonamide 856

N-2-,N-2-dimethyl-N-(3-{[(3-{[4- (methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)glycinamide 857

N-[3-(1H-indazol-6-ylamino)quinoxalin-2- yl]-3-nitrobenzenesulfonamide858

N-{4-(methyloxy)-3-[(3-{[(3- nitrophenyl)sulfonyl]amino}quinoxalin-2-yl)amino]phenyl}acetamide 859

N-{3-[(4-methylpyridin-3- yl)amino]quinoxalin-2-yl}-3-nitrobenzenesulfonamide 860

N-(3-{[2,3- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-nitrobenzenesulfonamide 861

N-(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-2-cyanobenzenesulfonamide 862

3-nitro-N-[3-(1H-pyrazolo[3,4-d]pyrimidin- 4-ylamino)quinoxalin-2-yl]benzenesulfonamide 863

N-[3-(1,3-benzoxazol-4-ylamino)quinoxalin-2-yl]-3-nitrobenzenesulfonamide 864

N-(3-{[2,6-difluoro-3- (methyloxy)phenyl]amino}quinoxalin-2-yl)-3-nitrobenzenesulfonamide 865

N-{3-[({3-[(4-fluoro-3- methylphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]phenyl}-N-2-,N-2- dimethylglycinamide 866

N-{3-[({3-[(3,5- dimethylphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]phenyl}-N-2-,N-2- dimethylglycinamide 867

N-(3-{[(3-{[2,4- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-,N-2- dimethylglycinamide 868

N-{3-[(3,5- dihydroxyphenyl)amino]quinoxalin-2-yl}-3-nitrobenzenesulfonamide 869

N-[3-({[3-(2,3-dihydro-1H-inden-5- ylamino)quinoxalin-2-yl]amino}sulfonyl)phenyl]-N-2-,N-2- dimethylglycinamide 870

N-(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2- yl)-4-[(1-methylethyl)oxy]benzenesulfonamide 871

N-(3-{[3,5- bis(methyloxy)phenyl]amino}quinoxalin-2-yl)biphenyl-4-sulfonamide 872

N-[3-({2-chloro-5- [(difluoromethyl)oxy]phenyl}amino)quinoxalin-2-yl]-3-nitrobenzenesulfonamide

In addition to the preferred embodiments recited hereinabove, alsopreferred are embodiments comprising combinations of preferredembodiments.

One of ordinary skill in the art would understand that certaincrystallized, protein-ligand complexes, in particular PI3K-ligandcomplexes, and their corresponding x-ray structure coordinates can beused to reveal new structural information useful for understanding thebiological activity of kinases as described herein. As well, the keystructural features of the aforementioned proteins, particularly, theshape of the ligand binding site, are useful in methods for designing oridentifying selective modulators of kinases and in solving thestructures of other proteins with similar features. Such protein-ligandcomplexes, having compounds of the invention as their ligand component,are an embodiment of the invention.

In one embodiment of the invention, the PI3K inhibitor is selected fromthe compounds in Table I having a PI3K-binding affinity of about 8 μM orless. In another embodiment, the PI3K inhibitor is selected from thecompounds in Table I having a PI3K-binding affinity of about 4 μM orless. In another embodiment, the PI3K inhibitor is selected from thecompounds in Table I having a PI3K-binding affinity of about 3 μM orless. In another embodiment, the PI3K inhibitor is selected from thecompounds in Table I having a PI3K-binding affinity of about 2 μM orless. In another embodiment, the PI3K inhibitor is selected from thecompounds in Table I having a PI3K-binding affinity of about 1.5 μM orless. In another embodiment, the PI3K inhibitor is selected from thecompounds in Table I having a PI3K-binding affinity of about 1 μM orless. In another embodiment, the PI3K inhibitor is selected from thecompounds in Table I having a PI3K-binding affinity of about 0.750 μM orless. In another embodiment, the PI3K inhibitor is selected from thecompounds in Table I having a PI3K-binding affinity of about 0.5 μM orless. In another embodiment, the PI3K inhibitor is selected from thecompounds in Table I having a PI3K-binding affinity of about 0.3 μM orless. In another embodiment, the PI3K inhibitor is selected from thecompounds in Table I having a PI3K-binding affinity of about 0.2 μM orless. In another embodiment, the PI3K inhibitor is selected from thecompounds in Table I having a PI3K-binding affinity of about 0.1 μM orless. In another embodiment, the PI3K inhibitor is selected from thecompounds in Table I having a PI3K-binding affinity of about 0.075 μM orless. In another embodiment, the PI3K inhibitor is selected from thecompounds in Table I having a PI3K-binding affinity of about 0.050 μM orless.

Synthetic Procedures

Fusion of the reagents at 180° C. in the presence of K₂CO₃ and metalliccopper was known to provide these compounds in low yield (S. H.Dandegaonker and C. K. Mesta, J. Med. Chem. 1965, 8, 884). New methodwas utilized that brief heating of the reagents in DMF in the presenceof K₂CO₃, commercially available 2,3-dichloroquinoxaline and substitutedarysulfonamides were formed in quantitative yields (S. V. Litvinenko, V.I. Savich, D. D. Bobrovnik, Chem. Heterocycl. Compd. (Engl. Transl),1994, 30, 340).

The displacement of the active chlorine atom in above compounds wastreated with 2,5-dimethoxy-phenylamine (nucleophile) in refluxing DMF togive the desired compounds in quantitative yields (S. V. Litvinenko, V.I. Savich, D. D. Bobrovnik, Chem. Heterocycl. Compd. (Engl. Transl),1994, 30, 340).

On the other hand, the syntheses of other quinoxaline derivatives werewell documented (W. C. Lumma, R. D. Hartman, J. Med. Chem. 1981, 24,93).

The following compounds were prepared in a manner similar to thatdescribed above:N-(3-{[2,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-nitrobenzenesulfonamide;N-(3-{[2,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-4-chlorobenzenesulfonamide;N-(3-chloroquinoxalin-2-yl)-3-nitrobenzenesulfonamide; and4-chloro-N-(3-chloroquinoxalin-2-yl)benzenesulfonamide.

Synthetic Examples Example 16-chloro-N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)pyridine-3-sulfonamide

6-chloropyridine-3-sulfonamide. 6-chloropyridine-3-sulfonyl chloride(4.1 g, 19.3 mmol) was stirred in ammonium hydroxide (30 mL) at roomtemperature for 2 hr. The reaction mixture was diluted with EtOAc (150mL) and any insoluble material filtered. The filtrate was transferred toa separatory funnel and the phases were separated. The aqueous phase wasfurther extracted with EtOAc (1×15 mL). The combined EtOAc extractionswere washed with H₂O (1×50 mL), saturated NaCl (1×50 mL), dried(Na2SO₄), and concentrated in vacuo to give6-chloropyridine-3-sulfonamide (2.58 g, 69%). MS (El) for C₅H₃Cl₂NO₂S:190.9 (MH−).

6-chloro-N-(3-chloroquinoxalin-2-yl)pyridine-3-sulfonamide.2,3-dichloroquinoxaline (1.09 g, 5.48 mmol),6-chloropyridine-3-sulfonamide (1.05 g, 5.45 mmol), K₂CO₃ (753 mg, 5.45mmol) and dry DMSO (30 mL) were combined and heated to 150 C withvigorous stirring for 3-4 hr. The reaction mixture was allowed to coolto room temperature, then poured into 1% AcOH in ice water (300 mL) withvigorous stirring. The resulting solids were filtered, washed with H₂Oand dried under high vacuum to give6-chloro-N-(3-chloroquinoxalin-2-yl)pyridine-3-sulfonamide (1.87g, 96%).MS (El) for C₁₃H₈Cl₂N₄O₂S: 354.99 (MH+).

6-chloro-N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)pyridine-3-sulfonamide.6-Chloro-N-(3-chloroquinoxalin-2-yl)pyridine-3-sulfonamide (775 mg, 2.2mmol), 3,5-dimethoxyaniline (355 mg, 2.3 mmol) and toluene (12 mL) werecombined and heated to 125 C with stirring overnight. The reaction wasallowed to cool to room temperature and diluted with Et₂O with vigorousstirring. The resulting solids were filtered, washed with Et₂O and driedto give6-chloro-N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)pyridine-3-sulfonamide(920 mg, 89%). 1H NMR (400 MHz, DMSO-d6) δ 12.20 (br s, 1H), 9.12 (d,1H), 9.01 (br s, 1H), 8.53 (dd, 1H), 7.91 (br d, 1H), 7.77 (d, 1H), 7.60(dd, 1H), 7.40 (m, 4H), 6.26 (m, 1H), 3.78 (s, 6H). MS (El) forC₂₁H₁₈ClN₅O₄S: 472.0 (MH+).

Example 2N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)-6-(2-(dimethylamino)ethylamino)pyridine-3-sulfonamide

N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)pyridine-3-sulfonamide(100 mg, 0.21 mmol), KHCO₃ (40 mg, 0.40 mmol),N¹,N¹-dimethylethane-1,2-diamine (225 μl, 2.0 mmol) and dry DMF (1.0 mL)were combined and heated to 130 C with stirring overnight. The reactionmixture was concentrated in vacuo and purified by preparative HPLC togiveN-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)-6-(2-(dimethylamino)ethylamino)pyridine-3-sulfonamide(21.0 mg, 19%). 1H NMR (400 MHz, DMSO-d6) δ 8.76 (br s, 1H), 8.63 (d,1H), 8.07 (dd, 1H), 7.40 (m, 1H), 7.34 (m, 1H), 7.28 (d, 2H), 7.14 (m,4H), 6.47 (d, 1H), 6.12 (m, 1H), 3.75 (s, 6H), 3.35 (m, 2H), 3.14 (m,2H), 2.74 (s, 6H). MS (El) for C₂₅H₂₉N₇O₄S: 524.1 (MH+).

Example 3N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)-6-(dimethylamino)pyridine-3-sulfonamide

The title compound was prepared according to the Examples above. 1H NMR(400 MHz, DMSO-d6) δ 12.00 (br s, 1H), 8.92 (br s, 1H), 8.74 (d, 1H),8.10 (dd, 1H), 7.38 (br s, 1H), 7.54 (m, 1H), 7.33 (m, 4H), 6.70 (d,1H), 6.22 (s, 1H), 3.77 (s, 6H), 3.08 (s, 6H). MS (EI) for C₂₃H₂₄N₆O₄S:481.1 (MH+).

Example 4N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)-6-(2-(dimethylamino)ethoxy)pyridine-3-sulfonamide

N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)pyridine-3-sulfonamide(100 mg, 0.21 mmol), 2-(dimethylamino)ethanol (50 μl, 0.50 mmol) and dryDMF were combined and 60% NaH in oil (80 mg, 2.0 mmol) added. Themixture was stirred at room temperature overnight. The reaction mixturewas concentrated in vacuo and purified by preparative HPLC to giveN-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)-6-(2-(dimethylamino)ethoxy)pyridine-3-sulfonamide(23 mg, 21%). 1H NMR (400 MHz, DMSO-d6) δ 8.78 (d, 1H), 8.73 (s, 1H),8.38 (dd, 1H), 7.40 (dd, 1H), 7.31 (m, 3H), 7.14 (m, 2H), 6.85 (d, 1H),6.12 (m, 1H), 4.56 (m, 2H), 3.76 (s, 6H), 3.43 (m, 2H), 2.77 (s, 6H). MS(EI) for C₂₅H₂₈N₆O₅S: 525.1 (MH+).

Example 5N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)-6-oxo-1,6-dihydropyridine-3-sulfonamide

N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)pyridine-3-sulfonamide(220 mg, 0.47 mmol), DMSO (5 mL), and 3N NaOH (5 mL) are combined andheated to 100 C overnight with stirring. Upon cooling to roomtemperature, the reaction mixture was diluted with H₂0 and the pH wasadjusted to 7.0 with 1N HCl. The resulting solid was filtered, washedwith H₂0, and air-dried. The solid was then sonicated in EtOAc,filtered, washed with EtOAc, and dried under high vacuum to giveN-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)-6-oxo-1,6-dihydropyridine-3-sulfonamide(190 mg, 90%). 1H NMR (400 MHz, DMSO-d6) δ 12.23 (br s, 1H), 12.10 (brs, 1H), 8.97 (s, 1H), 8.23 (s, 1H), 7.95 (m, 2H), 7.59 (m, 1H), 7.37 (m,4H), 6.43 (d, 1H), 6.25 (s, 1H), 3.77 (s, 6H). MS (EI) for C₂₁H₁₉N₅O₅S:454.0 (MH+).

The following title compounds were prepared according to the aboveExamples.

Example 6N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)-6-oxo-1,6-dihydropyridine-3-sulfonamide

1H NMR (400 MHz, DMSO-d6) δ 12.22 (br s, 1H), 12.10 (br s, 1H), 9.16 (s,1H), 8.60 (s, 1H), 8.14 (d, 1H), 7.94 (m, 1H), 7.85 (dd, 1H), 7.62 (m,1H), 7.40 (m, 3H) 6.69 (dd, 1H), 6.43 (d, 1H), 3.81 (s, 3H). MS (EI) forC₂₀H₁₆ClN₅O₄S: 456.0 (MH−).

Example 75-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)-N-(2-(dimethylamino)ethyl)-2-methoxybenzamide

1H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 8.95 (d, 1H), 8.57 (d, 1H),8.28 (t, 1H), 8.14 (dd, 1H), 7.46 (dd, 1H), 7.39 (m, 2H), 7.17 (m, 4H),6.60 (dd, 1H), 3.89 (s, 3H), 3.82 (s, 3H), 3.38 (m, 2H), 2.43 (m, 2H),2.21 (s, 6H). MS (EI) for C₂₇H₂₉ClN₆O₅S: 585.3 (MH+).

Example 85-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)-N-(2-(dimethylamino)ethyl)-2-fluorobenzamide

1H NMR (400 MHz, DMSO-d6) δ 9.40 (br s, 1H), 9.16 (s, 1H), 8.73 (m, 1H),8.67 (d, 1H), 8.36 (dd, 1H), 8.26 (m, 1H), 7.94 (br s, 1H), 7.66 (m,1H), 7.59 (t, 1H), 7.43 (m, 3H), 6.71 (dd, 1H), 3.83 (s, 3H), 3.62 (m,2H), 3.27 (m, 2H), 2.85 (d, 6H). MS (EI) for C₂₆H₂₆ClFN₆O₄S: 573.1(MH+).

Example 9N-(2-chloro-5-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(methylamino)acetamide

The title compound was prepared according to the Examples above. 1H NMR(400 MHz, DMSO-d6) δ 10.50 (s, 1H), 9.14 (s, 1H), 9.03 (m, 2H), 8.63 (d,1H), 8.44 (d, 1H), 7.98 (m, 1H), 7.91 (dd, 1H), 7.80 (d, 1H), 7.67 (m,1H), 7.44 (m, 3H), 6.71 (dd, 1H), 4.06 (m, 2H), 3.83 (s, 3H), 2.64 (t,3H). MS (EI) for C₂₄H₂₂Cl₂N₆O₄S: 561.0 (MH+).

Example 10(S)-2-amino-N-(3-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)propanamidehydrochloride

1H NMR (400 MHz, CD3OD) δ 8.72-8.71 (d, 1H), 8.48-8.46 (t, 1H),7.86-7.84 (m, 1H), 7.80-7.78 (m, 1H), 7.63-7.59 (m, 2H), 7.58-7.55 (t,1H), 7.41-7.38 (m, 2H), 7.24-7.22 (d, 1H), 6.60-6.58 (dd, 1H), 4.10-4.04(q, 1H), 3.83 (s, 3H), 1.61-1.60 (d, 3H); MS (EI) for C₂₄H₂₃ClN₆O₄S.HCl:527.2 (MH+).

Example 11(S)-2-amino-N-(3-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)butanamidehydrochloride

1H NMR (400 MHz, CD3OD) δ 8.74-8.73 (d, 1H), 8.80-8.47 (t, 1H),7.87-7.85 (m, 1H), 7.80-7.78 (m, 1H), 7.67-7.61 (m, 2H), 7.59-7.55 (t,1H), 7.42-7.39 (m, 2H), 7.26-7.24 (d, 1H), 6.62-6.59 (dd, 1H), 3.96-3.93(t, 1H), 3.84 (s, 3H), 2.02-1.94 (m, 2H, 1.09-1.06 (t, 3H); MS (EI) forC₂₅H₂₅ClN₆O₄S.HCl: 541.3 (MH+).

Example 12(S)-N-(3-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)pyrrolidine-2-carboxamidehydrochloride

1H NMR (400 MHz, CD3OD) δ 8.78-8.77 (d, 1H), 8.47-8.46 (t, 1H),7.87-7.85 (m, 1H), 7.80-7.75 (m, 1H), 7.69-7.65 (m, 2H), 7.59-7.55 (t,1H), 7.45-7.41 (m, 2H), 7.31-7.28 (d, 1H), 6.65-6.63 (dd, 1H), 4.42-4.38(m, 1H), 3.86 (s, 3H), 3.48-3.42 (m, 2H), 2.55-2.49 (m, 1H), 2.18-2.08(m, 3H); MS (EI) for C₂₆H₂₅ClN₆O₄S.HCl: 553.3 (MH+).

Example 13(S)-N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)pyrrolidine-2-carboxamidehydrochloride

1H NMR (400 MHz, CD3OD) δ 10.62 (br s, 1H), 8.50-8.49 (t, 1H), 7.90-7.87(m, 1H), 7.76-7.73 (m, 1H), 7.63-7.58 (m, 3H), 7.43-7.35 (m, 2H), 7.14(s, 2H), 6.27-6.26 (t, 1H), 4.43-4.38 (m, 1H), 3.78 (s, 6H), 3.48-3.41(m, 1H), 3.40-3.36 (m, 1H(, 2.54-2.48 (m, 1H), 2.19-2.05 (m, 3H); MS(EI) for C₂₇H₂₈N₆O₅S.HCl: 549.3 (MH+).

Example 14(R)-2-amino-N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-hydroxypropanamidehydrochloride

1H NMR (400 MHz, CD3OD) δ 8.49-8.48 (t, 1H), 7.89-7.87 (m, 1H),7.75-7.72 (m, 1H), 7.65-7.62 (m, 2H), 7.62-7.55 (t, 1H), 7.44-7.38 (m,2H), 7.23-7.22 (d, 2H), 6.27-6.26 (t, 1H), 4.07-4.05 (m, 1H), 3.99-3.93(m, 2H), 3.80 (s, 6H); MS (EI) for C₂₅H₂₆N₆O₆S.HCl: 539.1 (MH+).

Example 15N-(3-(N-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)piperidine-3-carboxamidehydrochloride

1H NMR (400 MHz, CD3OD) δ 8.79-8.78 (d, 1H), 8.45 (m, 1H), 7.83-7.81 (d,1H), 7.76-7.74 (m, 1H), 7.636 (m, 2H), 7.54-7.50 (t, 1H), 7.41 (m, 2H),7.30-7.28 (d, 1H), 6.65-6.62 (dd, 1H), 3.86 (s, 3H), 3.40-3.32 (m, 2H),3.20-3.13 (m, 3H), 2.93 (m, 1H), 2.15-2.11 (m, 1H), 1.98-1.93 (m, 2H),1.83 (m, 1H); MS (EI) for C₂₇H₂₇ClN₆O₄S.HCl: 567.3 (MH+).

Example 16(S)-2-amino-N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)butanamidehydrochloride

MS (EI) for C₂₆H₂₈N₆O₅S.HCl: 537.1 (MH+).

Example 17(R)-N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)pyrrolidine-2-carboxamidehydrochloride

MS (EI) for C₂₇H₂₈N₆O₅S.HCl: 549.1 (MH+).

Example 18(R)-N-(3-(N-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)pyrrolidine-2-carboxamidehydrochloride

MS (EI) for C₂₆H₂₅ClN₆O₄S.HCl: 553 (MH+).

Example 19N-(3-(N-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)morpholine-4-carboxamide

MS (EI) for C₂₆H₂₅ClN₆O₅S: 567 (MH−).

Example 20N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(dimethylamino)acetamide

MS (EI) for C₂₆H₂₈N₆O₅S: 535.1 (MH−).

Example 21(S)-2-amino-N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)propanamidehydrochloride

(S)-tert-butyl1-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenylamino)-1-oxopropan-2-ylcarbamate.3-amino-N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)benzenesulfonamide(1.1 mmol, 500 mg), (L)-Boc-Ala-OH (1.5 mmol, 284 mg), dichloromethane(15 mL), DMF (10 mL), DIEA (2 mmol, 330 ul), and HATU (2 mmol, 760 mg)stirred at r.t. over night. The crude mixture was column purified using1/1 ethyl acetate/hexanes on silica to gave 160 mg.

(S)-2-amino-N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)propanamidehydrochloride. 4 M HCl is dioxane (10 mL) was added to a solution of(S)-tert-butyl1-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenylamino)-1-oxopropan-2-ylcarbamate(160 mg) and DCM (15 mL). The mixture was stirred at r.t. for 3 hours.The solvent decanted and ether added to the solid, ether decanted togave 80 mg product as HCl salt. 1H NMR (400 MHz, CD3OD) δ 8.50-8.49 (t,1H), 7.89-7.87 (m, 1H), 7.74-7.72 (m, 1H), 7.61-7.5 (m, 3H), 7.40-7.36(m, 2H), 7.21-7.20 (d, 2H), 6.23-6.21 (t, 1H), 4.09-4.03 (q, 1H), 3.78(s, 6H), 1.60-1.58 (d, 3H); MS (EI) for C₂₅H₂₆N₆O₅S.HCl: 523.1 (MH+).

The following title compounds were prepared according to the aboveExamples.

Example 224-chloro-N-(3-(2,5-dimethoxyphenylamino)quinoxalin-2-yl)benzenesulfonamide

1H NMR (400 MHz, DMSO-d6) δ 9.18 (s, 1H), 8.78 (s, 1H), 8.40-8.60 (m,3H), 7.98 (t, 2H), 7.62 (d, 1H), 7.41 (m, 2H), 6.98 (d, 1H), 6.59 (d,1H), 3.78 (s, 3H), 3.76 (s, 3H); MS (EI) for C₂₂H₁₉N₅O₆S: 482.1 (MH+).

Example 23N-(3-(2,5-dimethoxyphenylamino)quinoxalin-2-yl)-3-nitrobenzenesulfonamide

1H NMR (400 MHz, CDCl₃) δ 12.68 (br s, 1H), 9.18 (s, 1H), 8.55 (s, 1H),8.08 (d, 2H), 7.98 (d, 1H), 7.78 (d, 2H), 7.62 (dd, 1H), 7.40 (m, 2H),7.00 (d, 1H), 6.60 (dd, 1H), 3.78 (s, 6H); MS (EI) for C₂₂H₁₉ClN₄O₄S:471.1 (MH+).

Example 24N-(3-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)-4-methylphenyl)-2-(dimethylamino)acetamide

1H NMR (400 MHz, DMSO-d6) δ 12.0 (br s, 1H), 10.6 (s, 1H), 10.0 (br s,1H), 9.52 (s, 1H), 8.91 (d, 1H), 8.25 (d, 1H), 7.69 (dd, 1H), 7.47 (m,1H), 7.39 (d, 1H), 7.16 (m, 3H), 6.01 (dd, 1H); MS (EI) forC₂₆H₂₇ClN₆O₄S: 555 (MH+).

Example 25(R)-2-amino-N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)propanamide

1H NMR (400 MHz, DMSO-d6) δ 10.2 (br s, 1H), 8.82 (s, 1H), 8.27 (m, 1H),7.75 (m, 2H), 7.33 (m, 5H), 7.13 (m, 2H), 6.14 (t, 1H), 3.77 (s, 6H),1.39 (d, 3H); MS (EI) for C₂₅H₂₆N₆O₅S: 523 (MH+).

Example 26N-(3-(N-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(methylamino)acetamide

1H NMR (400 MHz, DMSO-d6) δ 10.6 (s, 1H), 9.48 (s, 1H), 8.95 (br s, 1H),8.75 (br s, 1H), 8.19 (br s, 1H), 7.77 (dd, 1H), 7.69 (dd, 1H), 7.41 (m,4H), 7.17 (m, 2H), 6.60 (dd, 1H), 3.91 (s, 2H), 3.82 (s, 6H), 2.62 (s,3H); MS (EI) for C₂₄H₂₃ClN₆O₄S: 527 (MH+).

Example 27(R)-2-amino-N-(3-(N-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)propanamide

1H NMR (400 MHz, DMSO-d6) δ 10.5 (s, 1H), 9.47 (s, 1H), 8.95 (d, 1H),8.22 (d, 2H), 8.14 (br s, 2H), 7.76 (m, 2H), 7.40 (m, 4H), 7.17 (m, 2H),6.60 (m, 1H), 3.97 (q, 1H), 3.96 (s, 3H), 1.45 (d, 3H); MS (EI) forC₂₄H₂₃ClN₆O₄S: 527 (MH+).

Example 282-amino-N-(3-(N-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-methylpropanamide

1H NMR (400 MHz, DMSO-d6) δ 10.1 (s, 1H), 9.46 (s, 1H), 8.95 (d, 1H),8.50 (br s, 1H), 8.27 (m, 1H), 7.81 (m, 2H), 7.47 (m, 1H), 7.37 (m, 3H),7.17 (m, 2H), 6.61 (dd, 1H), 3.83 (s, 3H), 1.60 (s, 6H); MS (EI) forC₂₅H₂₅ClN₆O₄S: 541 (MH+).

Example 292-amino-N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-methylpropanamide

1H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 8.89 (s, 1H), 8.32 (br s,4H), 7.92 (m, 3H), 7.59 (m, 2H), 7.37 (m, 4H), 6.24 (s, 1H), 3.76 (s,6H), 1.61 (s, 6H); MS (EI) for C₂₆H₂₈N₆O₅S: 537 (MH+).

Example 30N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)-4-methylphenyl)-2-(dimethylamino)acetamide

1H NMR (400 MHz, DMSO-d6) δ 10.58 (s, 1H), 9.80 (br s, 1H), 8.85 (s,1H), 8.25 (s, 1H), 7.67 (dd, 1H), 7.30 (m, 7H), 6.16 (m, 1H), 4.02 (brs, 2H), 3.77 (s, 6H), 2.81 (s, 6H), 2.54 (s, 3H); MS (EI) forC₂₇H₃₀N₆O₅S: 551 (MH+).

Example 31N-(3-(N-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-((2-(dimethylamino)ethyl)(methyl)amino)acetamide

1H NMR (400 MHz, DMSO-d6) δ 10.0 (s, 1H), 9.48 (s, 1H), 8.96 (d, 1H),8.16 (m, 1H), 7.76 (m, 2H), 7.39 (m, 4H), 7.17 (m, 2H), 6.61 (dd, 1H),3.82 (s, 3H), 3.40 (br s, 2H), 2.94 (br s, 2H), 2.71 (br t, 2H), 2.60(s, 6H), 2.33 (s, 3H); MS (EI) for C₂₈H₃₂ClN₇O₄S: 598 (MH+).

Example 322-amino-N-(3-(N-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide

1H NMR (400 MHz, DMSO-d6) δ 10.5 (s, 1H), 9.48 (s, 1H), 8.94 (s, 1H),8.15 (s, 1H), 8.06 (br s, 3H), 7.74 (m, 2H), 7.39 (m, 4H), 7.18 (m, 2H),6.61 (dd, 1H), 3.83 (s, 3H), 3.77 (s, 2H); MS (EI) for C₂₃H₂₁ClN₆O₄S:513 (MH+).

Example 33N-(3-(N-(3-(2-acetyl-5-methoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(dimethylamino)acetamide

1H NMR (400 MHz, DMSO-d6) δ 12.4 (s, 1H), 10.5 (s, 1H), 9.27 (s, 1H),8.25 (s, 1H), 8.01 (d, 1H), 7.82 (d, 1H), 7.71 (d, 1H), 7.42 (m, 3H),7.21 (m, 2H), 6.63 (dd, 1H), 3.91 (m, 5H), 2.75 (s, 6H), 2.61 (s, 3H);MS (EI) for C₂₇H₂₈N₆O₅S: 549 (MH+).

Example 34N-(3-(N-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)formamide

1H NMR (400 MHz, DMSO-d6) δ 12.6 (s, 1H), 10.5 (s, 1H), 9.16 (s, 1H),8.53 (br s, 1H), 8.35 (m, 2H), 8.02 (s, 1H), 7.56 (m, 7H), 6.70 (dd,1H), 3.83 (s, 3H); MS (EI) for C₂₂H₁₈ClN₅O₄S: 484 (MH+).

Example 352-amino-N-(5-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)-2-methylphenyl)acetamide

1H NMR (400 MHz, DMSO-d6) δ 12.4 (s, 1H), 10.1 (br s, 1H), 8.82 (s, 1H),8.20 (m, 3H), 7.82 (m, 1H), 7.30 (m, 6H), 6.20 (s, 1H), 3.85 (s, 2H),3.77 (s, 6H), 2.26 (s, 3H); MS (EI) for C₂₅H₂₆N₆O₅S: 523 (MH+).

Example 36N-(3-(N-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-methyl-2-(methylamino)propanamide

1H NMR (400 MHz, DMSO-d6) δ 10.09 (s, 1H), 9.46 (s, 1H), 8.95 (m, 3H),8.28 (s, 1H), 7.81 (m, 2H), 7.41 (m, 4H), 7.17 (m, 2H), 6.60 (dd, 1H),3.82 (s, 3H), 2.53 (s, 3H), 1.60 (s, 6H); MS (EI) for C₂₆H₂₇ClN₆O₄S: 555(MH+).

Example 37(S)-N-(3-(N-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(methylamino)propanamide

1H NMR (400 MHz, DMSO-d6) δ 10.61 (s, 1H), 9.47 (s, 1H), 8.95 (s, 1H),8.82 (br s, 2H), 8.27 (m, 1H), 7.74 (m, 2H), 7.42 (m, 4H), 7.17 (m, 2H),6.60 (dd, 1H), 3.90 (m, 1H), 3.82 (s, 3H), 2.59 (s, 3H), 1.49 (d, 3H);MS (EI) for C₂₅H₂₅ClN₆O₄S: 541 (MH+).

Example 383-amino-N-(5-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)-2-methylphenyl)propanamide

1H NMR (400 MHz, DMSO-d6) δ 12.25 (s, 1H), 9.77 (s, 1H), 8.82 (s, 1H),7.84 (m, 5H), 7.50 (d, 1H), 7.37 (m, 5H), 6.22 (m, 1H), 3.74 (s, 6H),3.08 (m, 2H), 2.77 (m, 2H), 2.27 (s, 3H); MS (EI) for C₂₆H₂₈N₆O₅S: 537(MH+).

Example 391-amino-N-(3-(N-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)cyclopropanecarboxamide

1H NMR (400 MHz, DMSO-d6) δ 9.54 (br s, 1H), 9.42 (s, 1H), 8.91 (s, 1H),8.21 (s, 1H), 8.20 (br s, 2H), 7.81 (m, 2H), 7.48 (m, 4H), 7.22 (m, 2H),6.61 (dd, 1H), 3.82 (s, 3H), 1.63 (m, 2H), 1.26 (m, 2H); MS (EI) forC₂₅H₂₃ClN₆O₄S: 539 (MH+).

Example 40(S)-2-amino-N-(3-(N-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-6-(dimethylamino)hexanamide

1H NMR (400 MHz, DMSO-d6) δ 9.47 (br s, 1H), 8.95 (d, 1H), 8.26 (m, 1H),7.73 (m, 2H), 7.30 (m, 4H), 7.26 (m, 4H), 7.16 (m, 2H), 6.59 (dd, 1H),3.82 (s, 3H), 3.34 (m, 1H), 2.20 (m, 2H), 2.09 (s, 6H), 1.50 (m, 6H); MS(EI) for C₂₉H₃₄ClN₇O₄S: 610 (MH+).

Example 411-amino-N-(3-(N-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)cyclopentanecarboxamide

1H NMR (400 MHz, DMSO-d6) δ 10.12 (br s, 1H), 9.46 (s, 1H), 8.95 (d,1H), 8.26 (m, 1H), 8.16 (m, 3H), 7.84 (m, 2H), 7.35 (m, 6H), 6.60 (dd,1H), 3.82 (s, 3H), 2.34 (m, 2H), 1.91 (m, 6H); MS (EI) forC₂₇H₂₇ClN₆O₄S: 567 (MH+).

Example 422-amino-N-(5-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)-2-methylphenyl)acetamideExampleN-(5-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)-2-methylphenyl)-2-(dimethylamino)acetamide

1H NMR (400 MHz, DMSO-d6) δ 12.0 (br s, 1H), 9.98 (s, 1H), 9.43 (s, 1H),8.91 (m, 1H), 8.08 (s, 1H), 7.84 (dd, 1H), 7.32 (m, 6H), 6.61 (dd, 1H),4.07 (s, 2H), 3.82 (s, 3H), 2.82 (s, 6H), 2.21 (s, 3H); MS (EI) forC₂₆H₂₇ClN₆O₄S: 555 (MH+).

Example 431-amino-N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)cyclobutanecarboxamide

1H NMR (400 MHz, DMSO-d6) δ 10.34 (br s, 1H), 8.81 (s, 1H), 8.49 (br s,3H), 8.34 (s, 1H), 7.83 (m, 2H), 7.43 (m, 3H), 7.31 (m, 2H), 7.16 (m,2H), 6.16 (s, 1H), 3.77 (s, 6H), 2.83 (m, 2H), 2.25 (m, 3H), 2.05 (m,1H); MS (EI) for C₂₇H₂₈N₆O₅S: 549 (MH+).

Example 44N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)-3-(3-(2-(dimethylamino)ethyl)ureido)benzenesulfonamide

1H NMR (400 MHz, DMSO-d6) δ 8.91 (br s, 1H), 8.81 (s, 1H), 8.08 (s, 1H),7.60 (s, 1H), 7.38 (m, 9H), 6.28 (m, 1H), 6.15 (s, 1H), 3.78 (s, 6H),3.40 (m, 2H), 3.08 (m, 2H), 2.74 (s, 6H); MS (EI) for C₂₇H₃₁N₇O₅S: 566(MH+).

Example 451-amino-N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)cyclopentanecarboxamide

1H NMR (400 MHz, DMSO-d6) δ 12.40 (br s, 1H), 10.58 (s, 1H), 8.46 (m,4H), 7.80 (m, 3H), 7.59 (m, 2H), 7.34 (m, 4H), 6.25 (m, 1H), 3.76 (s,6H), 2.35 (m, 2H), 1.90 (m, 8H); MS (EI) for C₂₈H₃₀N₆O₅S: 563 (MH+).

Example 461-amino-N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)cyclopropanecarboxamide

1H NMR (400 MHz, DMSO-d6) δ 9.54 (br s, 1H), 8.84 (s, 1H), 8.29 (s, 1H),7.75 (m, 2H), 7.39 (m, 6H), 7.17 (m, 2H), 6.16 (m, 1H), 3.78 (s, 6H),1.52 (m, 2H), 1.17 (m, 2H); MS (EI) for C₂₆H₂₆N₆O₅S: 535 (MH+).

Example 47 2-(dimethylamino)ethyl3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenylcarbamate

1H NMR (400 MHz, DMSO-d6) δ 9.78 (br s, 1H), 8.79 (s, 1H), 8.19 (s, 1H),7.66 (d, 1H), 7.31 (m, 9H), 6.14 (m, 1H), 4.17 (t, 2H), 3.78 (s, 6H),2.54 (t, 2H), 2.21 (s, 6H): MS (EI) for C₂₇H₃₀N₆O₆S: 567 (MH+).

Example 484-amino-N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)tetrahydro-2H-pyran-4-carboxamide

1H NMR (400 MHz, DMSO-d6) δ 12.2 (br s, 1H), 10.6 (s, 1H), 8.74 (m, 5H),7.93 (m, 2H), 7.47 (m, 6H), 6.24 (m, 1H), 3.77 (m, 10H), 2.45 (m, 2H),1.81 (m, 2H); MS (EI) for C₂₈H₃₀N₆O₆S: 579 (MH+).

Example 49N1-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2-yl)-N3-(2-(dimethylamino)ethyl)benzene-1,3-disulfonamide

1H NMR (400 MHz, DMSO-d6) δ 9.35 (m, 2H), 8.92 (m, 1H), 8.64 (s, 1H),8.30 (m, 1H), 8.11 (s, 1H), 7.86 (m, 1H), 7.68 (m, 1H), 7.49 (s, 1H),7.42 (m, 2H), 7.21 (m, 2H), 6.61 (m, 1H), 3.82 (s, 3H), 3.05 (m, 4H),2.74 (s, 6H); MS (EI) for C₂₅H₂₇ClN₆O₅S₂: 591 (MH+).

Example 50N1-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2-yl)-N3-(3-(dimethylamino)propyl)benzene-1,3-disulfonamide

1H NMR (400 MHz, DMSO-d6) δ 9.38 (m, 2H), 8.90 (m, 1H), 8.60 (s, 1H),8.32 (m, 1H), 8.12 (s, 1H), 7.88 (m, 1H), 7.72 (m, 1H), 7.59 (s, 1H),7.40 (m, 2H), 7.20 (m, 2H), 6.67 (m, 1H), 3.82 (s, 3H), 2.97 (m, 2H),2.78 (m, 2H), 2.71 (s, 6H), 1.70 (m, 2H); MS (EI) for C₂₆H₂₉ClN₆O₅S₂:605 (MH+).

Example 51N-(3-(N-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)-4-methylphenyl)-2-(methylamino)acetamide

MS (EI) for C₂₅H₂₅ClN₆O₄S: 541.0 (MH+).

Example 52(S)-2-amino-N-(3-(N-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)-4-methylphenyl)propanamide

MS (EI) for C₂₅H₂₅ClN₆O₄S: 541.2 (MH+).

Example 53(R)-2-amino-N-(3-(N-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)-4-methylphenyl)propanamide

MS (EI) for C₂₅H₂₅ClN₆O₄S: 541.0 (MH+).

Example 54(S)-N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(methylamino)propanamide

MS (EI) for C₂₆H₂₈N₆O₅S: 537.1 (MH+).

Example 55(R)-N-(3-(N-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(methylamino)propanamide

MS (EI) for C₂₅H₂₅ClN₆O₄S: 541.1 (MH+).

Example 56(R)-N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(methylamino)propanamide

MS (EI) for C₂₆H₂₈N₆O₅S: 537.3 (MH+).

Example 57N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)piperidine-2-carboxamide

MS (EI) for C₂₈H₃₀N₆O₅S: 563.1 (MH+).

Example 58N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(2-(dimethylamino)ethylamino)acetamide

MS (EI) for C₂₈H₃₃N₇O₅S: 580.1 (MH+).

Example 59N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(4-(methylamino)piperidin-1-yl)acetamide

MS (EI) for C₃₀H₃₅N₇O₆S: 606.1 (MH+).

Example 60N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-((3-(dimethylamino)propyl)(methyl)amino)acetamide

MS (EI) for C₃₀H₃₇N₇O₅S: 608.1 (MH+).

Example 612-(1,4′-bipiperidin-1′-yl)-N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide

MS (EI) for C₃₄H₄₁N₇O₅S: 660.1 (MH+).

Example 62 tert-butyl2-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenylcarbamoyl)piperidine-1-carboxylate

MS (EI) for C₃₃H₃₈N₆O₇S: 663.1 (MH+).

Example 633-(N-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)-N-(1-(dimethylamino)propan-2-yl)benzamide

MS (EI) for C₂₇H₂₉ClN₆O₄S: 569.0 (MH+).

Example 643-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-[2-(dimethylamino)ethyl]benzamide

3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}benzoicacid. To a solution ofN-(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-cyanobenzenesulfonamide(6.02 g, 12.95 mmol) in methanol (20 mL) and 1,4-dioxane (20 mL) wasadded 6.0 N aqueous sodium hydroxide (40 mL) at room temperature. Thesolution was stirred at 90° C. for 3.5 h. The reaction was cooled toroom temperature and neutralized slowly by adding 2.0 N hydrochloricacid until the pH of the solution became in the 2-3 range at 0° C. Thesolution was diluted with ethyl acetate (300 mL). The organic layer waswashed with saturated aqueous sodium chloride (50 mL) and dried overmagnesium sulfate. Filtration and concentration at reduced pressureafforded3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}benzoicacid (5.921 g, 94%). MS (EI) for C₂₂H₁₇ClN₄O₅S: 485.0 (MH+)

3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-[2-(dimethylamino)ethyl]benzamide.To a solution of3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}benzoicacid (0.20 g, 0.42 mmol) in dimethylformamide (4 mL) were added2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATU, 0.32 g, 0.83 mmol) andN-ethyldiisopropylamine (DIEA, 0.13 g, 1.04 mmol) at room temperature.The reaction was stirred for 15 min beforeN,N-dimethylethane-1,2-diamine (73 mg, 0.83 mmol) was added. Thereaction mixture was allowed to stir overnight. The reaction was dilutedwith ethyl acetate (200 mL) and washed with water (50 mL), saturatedaqueous sodium bicarbonate (40 mL), 1.0 N aqueous hydrochloric acid (30mL), and saturated aqueous sodium chloride (25 mL). The organic layerwas dried over magnesium sulfate, filtered and concentrated at reducedpressure to afford3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-[2-(dimethylamino)ethyl]benzamide(0.20 g, 87%) as yellow solid. MS (EI) for C₂₆H₂₇ClN₆O₄S: 555.1 (MH+).

The following title compounds were prepared according to the aboveExamples.

Example 653-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)-N-(2-(dimethylamino)ethyl)benzamide

MS (EI) for C₂₇H₃₀N₆O₅S: 551.1 (MH+).

Example 663-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)-N-(2-(dimethylamino)ethyl)-N-methylbenzamide

MS (EI) for C₂₇H₂₉ClN₆O₄S: 569.1 (MH+).

Example 673-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)-N-(2-(dimethylamino)ethyl)-N-methylbenzamide

MS (EI) for C₂₈H₃₂N₆O₅S: 565.1 (MH+).

Example 693-(N-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)benzamide

MS (EI) for C₂₂H₁₈ClN₅O₄S: 484.0 (MH+).

Example 703-(N-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)benzoicacid

MS (EI) for C₂₂H₁₇ClN₄O₅S: 485.0 (MH+).

Example 713-(N-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)-N-(2-morpholinoethyl)benzamide

MS (EI) for C₂₈H₂₉ClN₆O₅S: 597.0 (MH+).

Example 723-(N-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)-N-methylbenzamide

MS (EI) for C₂₃H₂₀ClN₅O₄S: 498.0 (MH+).

Example 733-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)benzoic acid

MS (EI) for C₂₃H₂₀N₄O₆S: 481.0 (MH+).

Example 743-(N-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)-N-morpholinobenzamide

MS (EI) for C₂₆H₂₅ClN₆O₅S: 569.0 (MH+).

Example 75N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)-3-cyanobenzenesulfonamide

MS (EI) for C₂₂H₁₆ClN₅O₃S: 465.9 (MH+).

Example 76N-(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-{5-[(dimethylamino)methyl]-1,3,4-oxadiazol-2-yl}benzenesulfonamide

To a solution of3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}benzoicacid (0.25 g, 0.52 mmol) in dimethylformamide (2.6 mL) were added2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATU, 0.25 g, 0.67 mmol) andN-ethyldiisopropylamine (DIEA, 0.11 g, 0.88 mmol) at room temperature.The reaction was stirred for 15 min before2-(dimethylamino)acetohydrazide (78 mg, 0.67 mmol) was added. Thereaction mixture was allowed to stir overnight. The reaction was dilutedwith ethyl acetate (200 mL) and washed with water (30 mL), saturatedaqueous sodium bicarbonate (30 mL), 1.0 N aqueous hydrochloric acid (20mL), and saturated aqueous sodium chloride (25 mL). The organic layerwas dried over magnesium sulfate, filtered and concentrated at reducedpressure to afford 180 mg of a coupled intermediate which was thenheated in phosphorus oxychloride (5 mL) at 100° C. for 4 h. The reactionwas cooled to room temperature and treated with ice water (50 mL) andextracted with dichloromethane (3×50 mL). The organic layer was driedover magnesium sulfate, filtered and concentrated at reduced pressure toafford a crude product which was subjected to reverse phase HPLC toaffordN-(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-{5-[(dimethylamino)methyl]-1,3,4-oxadiazol-2-yl}benzenesulfonamide(16 mg, 5%) as yellow solid. MS (EI) for C₂₆H₂₄ClN₇O₄S: 566.0 (MH+).

Example 78N-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-(2H-tetrazol-5-yl)benzenesulfonamide

To a stirred solution of3-cyano-N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)benzenesulfonamide(0.20 g, 0.44 mmol) in dimethylformamide (1.2 mL) at 50° C. were addedsodium azide (0.11 g, 1.76 mmol) and ammonium chloride (94 mg, 1.76mmol). The crude mixture was heated at 100° C. overnight. The reactionwas cooled to room temperature treated with ice water (20 mL) followedby concentrated hydrochloric acid (10 mL). The solid obtained wasfiltered under reduced pressure and washed with hexane (20 mL), diethylether (20 mL), and ethyl acetate (5 mL) to affordN-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-(2H-tetrazol-5-yl)benzenesulfonamide(55 mg, 25%) as light yellow solid. MS (EI) for C₂₃H₂₀N₈O₄S: 505.0(MH+).

The following title compounds were prepared according to the aboveExamples.

Example 773-cyano-N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)benzenesulfonamide

MS (EI) for C₂₃H₁₉N₅O₄S: 462.3 (MH+).

Example 79N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(4-(dimethylamino)piperidin-1-yl)acetamide

MS (EI) for C₃₁H₃₇N₇O₅S: 620.1 (MH+).

Example 80N-(3-(2,5-dimethoxyphenylamino)quinoxalin-2-yl)-3-fluorobenzenesulfonamide

MS (EI) for C₂₂H₁₉FN₄O₄S: 456.0 (MH+).

Example 813-bromo-N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)benzenesulfonamide

MS (EI) for C₂₂H₁₉BrN₄O₄S: 516.9 (MH+).

Example 823-bromo-N-(3-(2,5-dimethoxy-phenylamino)quinoxalin-2-yl)benzenesulfonamide

MS (EI) for C₂₂H₁₉BrN₄O₄S: 516.9 (MH+).

Example 83 N-(3-(3-methoxyphenylamino)quinoxalin-2-yl)benzenesulfonamide

MS (EI) for C₂₁H₁₈N₄O₃S: 407.0 (MH+).

Example 84N-(3-(morpholinoamino)quinoxalin-2-yl)-3-nitrobenzenesulfonamide

MS (EI) for C₁₈H₁₈N₆O₅S: 431.0 (MH+).

Example 853-nitro-N-(3-(tetrahydro-2H-pyran-4-ylamino)quinoxalin-2-yl)benzenesulfonamide

MS (EI) for C₁₉H₁₉N₅O₅S: 430.0 (MH+)

Example 86N-(3-(4-fluoro-3-methoxyphenylamino)quinoxalin-2-yl)benzenesulfonamide

MS (EI) for C₂₁H₁₇FN₄O₃S: 425.0 (MH+).

Example 87N-(3-(2,5-dimethoxyphenylamino)quinoxalin-2-yl)-4-methoxybenzenesulfonamide

MS (EI) for C₂₃H₂₂N₄O₅S: 467.0 (MH+).

Example 88N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)-4-methoxybenzenesulfonamide

MS (EI) for C₂₃H₂₂N₄O₅S: 467.0 (MH+).

Example 89N-(3-(4-chloro-3-methoxyphenylamino)quinoxalin-2-yl)benzenesulfonamide

MS (EI) for C₂₁H₁₇ClN₄O₃S: 440.9 (MH+).

Example 90 N-(3-(2-methoxyphenylamino)quinoxalin-2-yl)benzenesulfonamide

MS (EI) for C₂₁H₁₈N₄O₃S: 407.0 (MH+).

Example 91N-(3-(3-(benzyloxy)phenylamino)quinoxalin-2-yl)benzenesulfonamide

MS (EI) for C₂₇H₂₂N₄O₃S: 483.0 (MH+).

Example 92 N-(3-(3-phenoxyphenylamino)quinoxalin-2-yl)benzenesulfonamide

MS (EI) for C₂₆H₂₀N₄O₃S: 469.0 (MH+).

Example 93N-(3-(3-methoxy-5-(trifluoromethyl)phenylamino)quinoxalin-2-yl)benzenesulfonamideMS (EI) for C₂₂H₁₇F₃N₄O₃S: 475.0 (MH+). Example 94N-(3-(2,5-diethoxyphenylamino)quinoxalin-2-yl)benzenesulfonamide

MS (EI) for C₂₄H₂₄N₄O₄S: 465.0 (MH+).

Example 95N-(3-(2′-methoxybiphenyl-4-ylamino)quinoxalin-2-yl)benzenesulfonamide

MS (EI) for C₂₇H₂₂N₄O₃S: 483.0 (MH+).

Example 96N-(3-(2-methoxy-5-methyl-phenylamino)quinoxalin-2-yl)benzenesulfonamide

MS (EI) for C₂₂H₂₀N₄O₃S: 421.0 (MH+).

Example 97 N-(3-(5-chloro-2-methoxyphenylamino)quinoxalin-2-yl)benzenesulfonamide

MS (EI) for C₂₁H₁₇ClN₄O₃S: 441.0 (MH+).

Example 98N-(3-(2-methoxy-5-(trifluoromethyl)-phenylamino)quinoxalin-2-yl)benzenesulfonamide

MS (EI) for C₂₂H₁₇F₃N₄O₃S: 475.0 (MH+).

Example 99N-(3-(2-methoxybiphenyl-4-ylamino)quinoxalin-2-yl)benzenesulfonamide

MS (EI) for C₂₇H₂₂N₄O₃S: 483.3 (MH+).

Example 100N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(dimethylamino)acetamide

1H NMR (400 MHz, DMSO) δ 12.4 (br s, 1H), 10.9 (s, 1H), 9.8 (s, 1H), 8.9(s, 1H), 8.3 (br s, 1H), 7.9 (d, 2H), 7.8 (d, 1H), 7.6 (t, 2H), 7.4 (q,2H), 7.3 (s, 1H), 6.25 (s, 1H), 4.15 (s, 2H), 3.8 (s, 6H), 2.9 (s, 6H).MS (EI) for C₂₆H₂₈N₆O₅S 2.0×C₂H₁O₂F₃: 537.1 (MH+).

Example 1012-(dimethylamino)-N-(3-(N-(3-(3-(2-(dimethylamino)acetamido)-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide

N-(3-chloroquinoxalin-2-yl)-3-nitrobenzenesulfonamide.2,3-Dichloroquinoxaline (26.1 g, 131.1 mmol), m-Nitrobenzene sulfonamide(26.5 g, 131.1 mmol) and potassium carbonate (18.1 g, 131.1) weredissolved in anhydrous DMSO (500 mL). The reaction was heated to 150° C.for 2 h. The reaction mixture was poured into water (400 mL), followedby addition of 2M HCl (60 mL). The product was extracted with EtOAc(3×500 mL). The organic layers were combined and washed water (2×500 mL)and brine (2×500 mL). The product was then dried with sodium sulfate togive N-(3-chloroquinoxalin-2-yl)-3-nitrobenzenesulfonamide. MS (EI) forC₁₄H₉ClN₄O₄S: 364.94, 366.97 (MH+)

N-(3-(3-methoxy-5-nitrophenylamino)quinoxalin-2-yl)-3-nitrobenzenesulfonamide.N-(3-chloroquinoxalin-2-yl)-3-nitrobenzenesulfonamide (700 mg, 1.92mmol), 3-methoxy-5-nitroaniline (645 mg, 3.84 mmol) and p-xylene (7 mL)were combined and heated to 140° C., then stirred for 16 hours at 130°C. The reaction was allowed to cool, placed in a sep funnel, dilutedwith DCM, and washed with 2M HCl and brine and concentrated in vacuo.The resulting solid was washed with Et₂O to giveN-(3-(3-methoxy-5-nitrophenylamino)quinoxalin-2-yl)-3-nitrobenzenesulfonamide(400 mg, 42%). MS (EI) for C₂₁H₁₆N₆O₇S: 496.94 (MH+)

3-amino-N-(3-(3-amino-5-methoxyphenylamino)quinoxalin-2-yl)benzenesulfonamide.N-(3-(3-Methoxy-5-nitrophenylamino)quinoxalin-2-yl)-3-nitrobenzenesulfonamide(400 mg, 0.81 mmol) was dissolved in 1:1 THF:EtOH (4 mL), to which wasadded formic acid (938 μl, 2.42 mmol) and potassium formate (203 mg,2.42 mmol). The system was flushed with nitrogen, and then 10% wt Pd/C(50 mg) was added. The reaction was then heated to 60° C. Once thereaction was determined complete by LC-MS, it was allowed to cool, andDMF was added for solubility. The solution was then filtered through anylon frit to remove the catalyst. The filtrate was diluted water andthe pH adjusted to 7 and extracted with DCM (2×) and EtOAc (2×). Allorganic layers were combined and evaporated to dryness to give3-amino-N-(3-(3-amino-5-methoxyphenylamino)quinoxalin-2-yl)benzenesulfonamide(330 mg, 93%). MS (EI) for C₂₁H₂₀N₆O₃S: 437.06 (MH+)

2-(dimethylamino)-N-(3-(N-(3-(3-(2-(dimethylamino)acetamido)-5-methoxyphenylamino)quinoxalin-2-yl)-sulfamoyl)phenyl)acetamide.3-Amino-N-(3-(3-amino-5-methoxyphenylamino)quinoxalin-2-yl)benzenesulfonamide(330 mg, 0.76 mmol), DMF (4 mL), N,N,-Dimethylglycine (312 mg, 3.02mmol), HATU (1.15 g, 3.02 mmol), and 1.29 (mL) (7.56 mmol) DIEA (1.29mL, 7.56 mmol) were combined and heated to 90° C., followed by heatingat 50° C. for over 16 hours. The reaction was allowed to cool, placedinto a sep. funnel diluted with water and aqueous LiCl and extractedwith EtOAc. The final compound was then purified by prep. HPLC to give2-(dimethylamino)-N-(3-(N-(3-(3-(2-(dimethylamino)acetamido)-5-methoxy-phenylamino)-quinoxalin-2-yl)sulfamoyl)phenyl)acetamide.1H NMR (400 MHz, CD3OD) δ 8.45 (t, 1H), 7.93 (t, 1H), 7.85-7.88 (m, 1H),7.70-7.74 (m, 1H), 7.65-7.68 (m, 1H), 7.58-7.62 (m, 1H), 7.58 (t, 1H),7.34-7.42 (m, 3H), 7.0 (t, 1H), 4.05 (d, 2H), 3.8 (s, 3H), 2.9-3.0 (d,12H). MS (EI) for C₂₉H₃₄N₈O₅S: 607.2 (MH+).

The following title compounds were prepared according to the aboveExamples.

Example 102N-(3-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(ethylamino)acetamide

1H NMR (400 MHz, DMSO) δ 10.8 (s, 1H), 9.20 (s, 1H), 8.84 (br s, 2H),8.64 (br s, 1H), 8.30 (s, 1H), 7.9-8.0 (br s, 1H), 7.80 (t, 2H),7.55-7.68 (m, 2H), 7.4 (d, 3H), 6.70 (m, 1H), 3.97 (br s, 2H), 3.83 (s,3H), 3.04 (br s, 2H), 1.3 (t, 3H). MS (EI) for C₂₅H₂₅ClN₆O₄S2.0×C₂H₁O₂F₃: 541.3, 543.2 (MH+).

Example 1032-(azetidin-1-yl)-N-(3-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide

1H NMR (400 MHz, DMSO) δ 10.8 (s, 1H), 10.2 (s, 1H), 9.2 (s, 1H), 8.7(s, 1H), 8.3 (s, 1H), 7.9-8.0 (br s, 1H), 7.80 (d, 1H), 7.72 (d, 1H),7.65 (br s, 1H), 7.56 (t, 1H), 7.40 (d, 3H), 6.70 (m, 1H), 4.28 (s, 2H),4.15 (m, 4H), 3.82 (s, 3H), 2.32 (br s, 1H). MS (EI) for C₂₆H₂₅ClN₆O₄S2.0×C₂H₁O₂F₃: 553.3, 555.2 (MH+).

Example 104N-(3-(N-(3-(2-bromo-5-methoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(methylamino)acetamide

The title compound was prepared according to the Examples above. 1H NMR(400 MHz, DMSO) δ 10.6 (s, 1H), 9.5 (s, 1H), 8.95 (d, 1H), 8.18 (t, 1H),7.78 (m, 1H), 7.70 (m, 1H), 7.54 (d, 1H), 7.46 (m, 1H), 7.38 (t, 1H),7.32 (d, 1H), 7.12-7.22 (m, 2H), 6.56 (m, 1H), 3.90 (s, 2H), 3.82 (s,3H), 2.62 (s, 3H). MS (EI) for C₂₄H₂₃BrN₆O₄S: 572.77, 570.90 (MH+).

Example 1052-(dimethylamino)-N-(3-(N-(3-(6-methoxy-quinolin-8-ylamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide

The title compound was prepared according to the Examples above. 1H NMR(400 MHz, DMSO) δ 10.9 (s, 1H), 10.6 (s, 1H), 9.13 (s, 1H), 8.80 (d,1H), 8.26-8.30 (m, 2H), 7.85 (d, 1H), 7.70 (d, 1H), 7.60 (q, 1H), 7.54(m, 1H), 7.44 (t, 2H), 7.20 (t, 2H), 6.80 (d, 1H), 4.00 (s, 2H), 3.94(s, 3H), 2.78 (s, 6H). MS (EI) for C₂₈H₂₇N₇O₄S: 558.3 (MH+).

Example 106N-(3-(N-(3-(2-bromo-5-methoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(dimethylamino)acetamide

The title compound was prepared according to the Examples above. 1H NMR(400 MHz, DMSO) δ 10.6 (s, 1H), 9.4 (s, 1H), 8.9 (s, 1H), 8.25 (s, 1H),7.78 (d, 1H), 7.70 (d, 1H), 7.54 (d, 1H), 7.48 (d, 1H), 7.40 (t, 2H),6.56 (d, 1H), 4.02 (s, 2H), 3.82 (s, 3H), 2.80 (s, 6H). MS (EI) forC₂₅H₂₅BrN₆O₄S: 586.79, 584.91 (MH+).

Example 107N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)-3-(hydroxyamino)benzenesulfonamide

MS (EI) for C₂₂H₂₁N₅O₅S: 468.1 (MH+).

Example 108N-(3-(N-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(2-fluoroethylamino)acetamide

The title compound was prepared according to the Examples above. 1H NMR(400 MHz, DMSO) δ 10.6 (s, 1H), 9.4 (s, 1H), 8.9 (d, 1H), 8.20 (s, 1H),7.78 (d, 1H), 7.70 (d, 1H), 7.48 (m, 1H), 7.36-7.44 (m, 3H), 7.20 (q,3H), 6.6 (m, 1H), 4.78 (t, 1H), 4.66 (t, 1H), 3.94 (s, 2H), 3.82 (s,3H), 3.4 (t, 1H), 3.3 (t, 1H). MS (EI) for C₂₅H₂₄ClFN₆O₄S: 559.2, 561.2(MH+).

Example 109N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)formamide

1H NMR (400 MHz, DMSO) δ 12.4 (br s, 1H), 10.5 (s, 1H), 8.90 (s, 1H),8.3 (s, 1H), 7.9 (br s, 1H), 7.85 (d, 1H), 7.75 (d, 1H), 7.5-7.6 (m,2H), 7.3-7.4 (m, 4H), 6.2 (s, 1H), 3.8 (s, 3H). MS (EI) for C₂₃H₂₁N₅O₅S:480.1 (MH+).

Example 110N-(3-(N-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(3-(dimethylamino)azetidin-1-yl)acetamide

1H NMR (400 MHz, DMSO) δ 10.2 (br s, 1H), 9.5 (s, 1H), 8.95 (d, 1H), 8.2(s, 1H), 7.75 (d, 1H), 7.65 (d, 1H), 7.45 (d, 1H), 7.40 (d, 1H),7.30-7.35 (t, 1H), 7.1-7.2 (q, 2H), 6.60 (m, 1H), 3.82 (s, 3H). MS (EI)for C₂₈H₃₀ClN₇O₄S: 480.1 (MH+).

Example 111N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(pyrrolidin-1-yl)acetamide

MS (EI) for C₂₈H₃₀N₆O₅S: 563.18 (MH+).

Example 1123-amino-N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)benzenesulfonamide

1H NMR (400 MHz, DMSO) δ 12.2 (br s, 1H), 8.85 (s, 1H), 7.90 (br s, 1H),7.50-7.60 (m, 1H), 7.3-7.4 (m, 4H), 7.2 (m, 3H), 6.74 (m, 1H), 6.24 (m,1H), 5.56 (br s, 2H), 3.76 (s, 6H). MS (EI) for C₂₂H₂₁N₅O₄S: 452.0(MH+).

Example 113N-(3-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(ethyl(methyl)amino)acetamide

1H NMR (400 MHz, DMSO) δ 12.0 (s, 1H), 10.6 (s, 1H), 9.65 (s, 1H), 9.5(s, 1H), 8.95 (s, 1H), 8.25 (s, 1H), 7.8 (d, 1H), 7.70 (d, 1H),7.45-7.50 (d, 1H), 7.3-7.4 (m, 3H), 7.2 (t, 2H), 6.60 (d, 1H), 4.02 (brs, 2H), 3.82 (s, 3H), 3.14 (br s, 2H), 2.80 (s, 3H) 1.2 (t, 3H). MS (EI)for C₂₆H₂₇ClN₆O₄S: 555.2, 557.3 (MH+).

Example 114N-(3-(N-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(3-(piperidin-1-yl)azetidin-1-yl)acetamide

MS (EI) for C₃₁H₃₄ClN₇O₄S 2.0×C₂H₁O₂F₃: 636.3, 638.3 (MH+).

Example 115N-(3-(N-(3-(3-fluoro-5-methoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(methylamino)acetamide

MS (EI) for C₂₄H₂₃FN₆O₄S: 511.04 (MH+).

Example 116N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-1-methylpiperidine-4-carboxamide

MS (EI) for C₂₉H₃₂N₆O₅S 1.0×C₂H₄O₂: 577.2 (MH+).

Example 117N-(3-(N-(3-(3-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(methylamino)acetamide

1H NMR (400 MHz, DMSO) δ 10.6 (s, 1H), 8.82 (s, 1H), 8.22 (t, 1H), 7.86(t, 1H), 7.76 (m, 1H), 7.66 (m, 1H), 7.46 (m, 1H), 7.41 (m, 1H), 7.38(t, 1H), 7.28 (m 1H), 7.24 (t, 1H), 7.12 (m, 2H), 6.56 (d, 1H), 3.88 (s,2H), 3.80 (s, 3H), 2.60 (s, 3H). MS (EI) for C₂₄H₂₄N₆O₄S: 492.99 (MH+).

Example 118N-(3-(N-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(2,2,2-trifluoroethylamino)acetamide

1H NMR (400 MHz, DMSO) δ 10.4 (s, 1H), 9.2 (s, 1H), 8.65 (s, 1H), 8.4(s, 1H), 8.00 (m, 1H), 7.80 (d, 1H), 7.75 (d, 1H), 7.65 (q, 1H), 7.55(t, 1H), 7.40-7.5 (m, 3H), 6.7 (m, 1H), 3.82 (s, 3H), 3.62 (br s, 2H),3.55 (br d, 2H). MS (EI) for C₂₅H₂₂ClF₃N₆O₄S 1.0×C₂H₁O₂F₃: 595.0, 597.0(MH+).

Example 119N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-(piperidin-1-yl)propanamide

MS (EI) for C₃₀H₃₄N₆O₅S: 591.2 (MH+).

Example 1203-amino-N-(3-(2,5-dimethoxy-phenylamino)quinoxalin-2-yl)benzenesulfonamide

1H NMR (400 MHz, DMSO) δ 12.4 (br s, 1H), 9.20 (s, 1H), 8.56 (d, 1H),7.95 (d, 1H), 7.62 (m, 1H), 7.38 (m, 2H), 7.24 (q, 2H), 7.14 (d, 1H),6.98 (d, 1H), 6.8 (m, 1H), 6.60 (m, 1H), 5.6 (br s, 2H), 3.78 (d, 6H).MS (EI) for C₂₂H₂₁N₅O₄S: 452.3 (MH+).

Example 121N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-4-(dimethylamino)butanamide

MS (EI) for C₂₈H₃₂N₆O₅S 1.0×C₂H₄O₂: 565.2 (MH+).

Example 1222-(dimethylamino)-N-(3-(N-(3-(3-fluoro-5-methoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide

1H NMR (400 MHz, DMSO) δ 10.9 (s, 1H), 9.8 (br s, 1H), 9.1 (s, 1H), 8.34(s, 1H), 7.90 (d, 1H), 7.76 (d, 1H), 7.52-7.68 (m, 4H), 7.40 (m, 2H),6.54 (m, 1H), 4.16 (s, 2H), 3.82 (s, 3H), 2.86 (s, 6H). MS (EI) forC₂₅H₂₅FN₆O₄S: 525.05 (MH+).

Example 123N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(piperidin-1-yl)acetamide

MS (EI) for C₂₉H₃₂N₆O₅S: 577.37 (MH+).

Example 1243-amino-N-(3-(2-chloro-5-hydroxy-phenylamino)quinoxalin-2-yl)benzenesulfonamide

MS (EI) for C₂₀H₁₆ClN₅O₃S 1.0×C₂H₁O₂F₃: 442.2, 444.2 (MH+).

Example 1252-(dimethylamino)-N-(3-(N-(3-(3-methoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide

1H NMR (400 MHz, DMSO) δ 10.5 (s, 1H), 8.8 (s, 1H), 8.25 (s, 1H), 7.83(t, 1H), 7.76 (d, 1H), 7.64 (d, 1H), 7.3-7.48 (m, 4H), 7.22 (t, 1H),7.12 (t, 2H), 6.56 (m, 1H), 3.96 (s, 2H), 3.78 (s, 3H), 2.76 (s, 6H). MS(EI) for C₂₅H₂₆N₆O₄S: 507.1 (MH+).

Example 126N-(3-(N-(3-(2-chloro-5-hydroxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(dimethylamino)acetamide

1H NMR (400 MHz, DMSO) δ 10.8 (s, 1H), 9.9 (s, 1H), 9.8 (s, 1H), 9.1 (s,1H), 8.55 (s, 1H), 8.34 (s, 1H), 7.9-8.0 (br s, 1H), 7.82 (d, 1H), 7.76(d, 1H), 7.52-7.66 (m, 2H), 7.42 (t, 1H), 7.26 (d, 1H), 6.50 (m, 1H),4.16 (s, 2H), 2.86 (s, 6H). MS (EI) for C₂₄H₂₃ClN₆O₄S: 527.1, 529.0(MH+).

Example 127N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-morpholinoacetamide

MS (EI) for C₂₈H₃₀N₆O₆S: 579.1 (MH+).

Example 1283-amino-N-(3-(6-methoxyquinolin-8-ylamino)quinoxalin-2-yl)benzenesulfonamide

MS (EI) for C₂₄H₂₀N₆O₃S: 473.0 (MH+).

Example 129N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)thiophene-2-sulfonamide

MS (EI) for C₂₀H₁₈N₄O₄S₂: 443.0 (MH+).

Example 130N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)-3-(methylamino)benzenesulfonamide

MS (EI) for C₂₃H₂₃N₅O₄S: 466.05 (MH+).

Example 1313-amino-N-(3-(3-methoxy-5-nitro-phenylamino)quinoxalin-2-yl)benzenesulfonamide

MS (EI) for C₂₁H₁₈N₆O₅S: 467.00 (MH+).

Example 1323-amino-N-(3-(3-fluoro-5-methoxy-phenylamino)quinoxalin-2-yl)benzenesulfonamide

MS (EI) for C₂₁H₁₈FN₅O₃S: 439.99 (MH+).

Example 1343-amino-N-(3-(3-amino-5-methoxy-phenylamino)quinoxalin-2-yl)benzenesulfonamide

MS (EI) for C₂₁H₂₀N₆O₃S: 437.2 (MH+).

Example 135N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)-3-(dimethylamino)benzenesulfonamide

MS (EI) for C₂₄H₂₅N₅O₄S: 480.04 (MH+).

Example 136N-(3-(2-chloro-6-methoxypyridin-4-ylamino)quinoxalin-2-yl)-3-nitrobenzenesulfonamide

MS (EI) for C₂₀H₁₅ClN₆O₅S: 496.94 (MH+).

Example 137N-(3-(6-methoxyquinolin-8-ylamino)quinoxalin-2-yl)-3-nitrobenzenesulfonamide

MS (EI) for C₂₄H₁₈N₆O₅S: 502.95 (MH+).

Example 1383-nitro-N-(3-(pyridin-4-ylamino)quinoxalin-2-yl)benzenesulfonamide

MS (EI) for C₁₉H₁₄N₆O₄S: 423.2 (MH+).

Example 139N-(3-(2,6-dichloropyridin-4-ylamino)quinoxalin-2-yl)-3-nitrobenzenesulfonamide

MS (EI) for C₁₉H₁₂Cl₂N₆O₄S: 491.1, 493.1 (MH+).

Example 140N-(3-(2-chloropyridin-4-ylamino)quinoxalin-2-yl)-3-nitrobenzenesulfonamide

MS (EI) for C₁₉H₁₃ClN₆O₄S: 456.93, 458.90 (MH+).

Example 141N-(3-(4,6-dimethoxypyrimidin-2-ylamino)quinoxalin-2-yl)-3-nitrobenzenesulfonamide

MS (EI) for C₂₀H₁₇N₇O₆S: 484.03 (MH+).

Example 142N-(3-(4-hydroxy-6-methoxypyrimidin-2-ylamino)quinoxalin-2-yl)-3-nitrobenzenesulfonamide

MS (EI) for C₁₉H₁₅N₇O₆S: 469.97 (MH+).

Example 143N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)-2-fluorobenzenesulfonamide

MS (EI) for C₂₂H₁₉FN₄O₄S: 455.3 (MH+).

Example 144N-(3-(2-bromo-5-methoxyphenylamino)quinoxalin-2-yl)-3-nitrobenzenesulfonamide

MS (EI) for C₂₁H₁₆BrN₅O₅S: 531.82, 532.84 (MH+).

Example 145N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)-4-methylbenzenesulfonamide

MS (EI) for C₂₃H₂₂N₄O₄S: 451.0 (MH+).

Example 146N-(3-(2,5-dimethoxyphenylamino)-7-methylquinoxalin-2-yl)benzenesulfonamide

MS (EI) for C₂₃H₂₂N₄O₄S: 451.0 (MH+).

Example 147N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)-3-nitrobenzenesulfonamide

MS (EI) for C₂₂H₁₉N₅O₆S: 481.9 (MH+).

Example 148N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide

MS (EI) for C₂₄H₂₃N₅O₅S: 494.0 (MH+).

Example 149N-(3-(2,5-dimethoxyphenylamino)quinoxalin-2-yl)-4-methylbenzenesulfonamide

MS (EI) for C₂₃H₂₂N₄O₄S: 451.0 (MH+).

Example 150N-(3-(3-fluoro-5-methoxy-phenylamino)quinoxalin-2-yl)-3-nitrobenzenesulfonamide

MS (EI) for C₂₁H₁₆FN₅O₅S: 470.0 (MH+).

Example 1514-bromo-N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)benzenesulfonamide

MS (EI) for C₂₂H₁₉BrN₄O₄S: 516.9, 514.9 (MH+).

Example 152N-(3-(3-methoxyphenylamino)quinoxalin-2-yl)-3-nitrobenzenesulfonamide

MS (EI) for C₂₁H₁₇N₅O₅S: 451.93 (MH+).

Example 153N-(3-(2-chloro-5-hydroxy-phenylamino)quinoxalin-2-yl)-3-nitrobenzenesulfonamide

MS (EI) for C₂₀H₁₄ClN₅O₅S: 472.15, 474.13 (MH+).

Example 154N-(3-(3-methoxy-5-nitro-phenylamino)quinoxalin-2-yl)-3-nitrobenzenesulfonamide

MS (EI) for C₂₁H₁₆N₆O₇S: 496.94 (MH+).

Example 155N-(3-(benzo[d][1,3]dioxol-5-ylamino)quinoxalin-2-yl)-3-nitrobenzenesulfonamide

MS (EI) for C₂₁H₁₅N₅O₆S: 466.2 (MH+).

Example 156N-(3-(3-hydroxyphenylamino)quinoxalin-2-yl)-3-nitrobenzenesulfonamide

MS (EI) for C₂₀H₁₅N₅O₅S: 438.16 (MH+).

Example 1573-nitro-N-(3-(3-(trifluoromethoxy)-phenylamino)quinoxalin-2-yl)benzenesulfonamide

MS (EI) for C₂₁H₁₄F₃N₅O₅S: 506.19 (MH+).

Example 1583-nitro-N-(3-(pyridin-3-ylamino)quinoxalin-2-yl)benzenesulfonamide

MS (EI) for C₁₉H₁₄N₆O₄S: 423.15 (MH+).

Example 159 3-(3-(3-nitrophenylsulfonamido)quinoxalin-2-ylamino)phenyldimethylcarbamate

MS (EI) for C₂₃H₂₀N₆O₆S: 509.01 (MH+).

Example 160N-(3-(2-chloropyridin-3-ylamino)quinoxalin-2-yl)-3-nitrobenzenesulfonamide

MS (EI) for C₁₉H₁₃ClN₆O₄S: 456.91 (MH+).

Example 161N-(3-(3-isopropoxyphenylamino)quinoxalin-2-yl)-3-nitrobenzenesulfonamide

MS (EI) for C₂₃H₂₁N₅O₅S: 480.3 (MH+).

Example 162N-(3-(3-hydroxy-2-methyl-phenylamino)quinoxalin-2-yl)-3-nitrobenzenesulfonamide

MS (EI) for C₂₁H₁₇N₅O₅S: 452.2 (MH+).

Example 163N-(3-(2,5-difluorophenylamino)quinoxalin-2-yl)-3-nitrobenzenesulfonamide

MS (EI) for C₂₀H₁₃F₂N₅O₄S: 458.2 (MH+).

Example 164N-(3-(3-(difluoromethoxy)phenylamino)quinoxalin-2-yl)-3-nitrobenzenesulfonamide

MS (EI) for C₂₁H₁₅F₂N₅O₅S: 488.2 (MH+).

Example 165N-(3-(2-methoxypyridin-3-ylamino)quinoxalin-2-yl)-3-nitrobenzenesulfonamide

MS (EI) for C₂₀H₁₆N₆O₅S: 453.01 (MH+).

Example 166N-(3-(3-ethoxyphenylamino)quinoxalin-2-yl)-3-nitrobenzenesulfonamide

MS (EI) for C₂₂H₁₉N₅O₅S: 466.2 (MH+).

Example 167N-(3-(2,2-difluorobenzo[d][1,3]dioxol-4-ylamino)quinoxalin-2-yl)-3-nitrobenzenesulfonamide

MS (EI) for C₂₁H₁₃F₂N₅O₆S: 502.2 (MH+).

Example 168N-(3-(3-(3-nitrophenylsulfonamido)quinoxalin-2-ylamino)phenyl)acetamide

MS (EI) for C₂₂H₁₈N₆O₅S: 479.2 (MH+).

Example 169N-(3-(4-amino-1H-indol-1-yl)quinoxalin-2-yl)-3-nitrobenzenesulfonamide

MS (EI) for C₂₂H₁₆N₆O₄S: 461.2 (MH+).

Example 170N-(3-(1H-indol-4-ylamino)quinoxalin-2-yl)-3-nitrobenzenesulfonamide

MS (EI) for C₂₂H₁₆N₆O₄S: 461.2 (MH+).

Example 171N-(3-(1H-indazol-6-ylamino)quinoxalin-2-yl)-3-nitrobenzenesulfonamide

MS (EI) for C₂₁H₁₅N₇O₄S: 461.96 (MH+).

Example 172N-(4-methoxy-3-(3-(3-nitro-phenylsulfonamido)quinoxalin-2-ylamino)phenyl)acetamide

MS (EI) for C₂₃H₂₀N₆O₆S: 508.97 (MH+).

Example 173N-(3-(4-methylpyridin-3-ylamino)quinoxalin-2-yl)-3-nitrobenzenesulfonamide

MS (EI) for C₂₀H₁₆N₆O₄S: 436.93 (MH+).

Example 174N-(3-(2,3-dimethoxyphenylamino)quinoxalin-2-yl)-3-nitrobenzenesulfonamide

MS (EI) for C₂₂H₁₉N₅O₆S: 481.94 (MH+).

Example 175N-(3-(1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)quinoxalin-2-yl)-3-nitrobenzenesulfonamide

MS (EI) for C₁₉H₁₃N₉O₄S: 463.96 (MH+).

Example 176N-(3-(benzo[d]oxazol-4-ylamino)quinoxalin-2-yl)-3-nitrobenzenesulfonamide

MS (EI) for C₂₁H₁₄N₆O₅S: 462.99 (MH+).

Example 177N-(3-(2,6-difluoro-3-methoxy-phenylamino)quinoxalin-2-yl)-3-nitrobenzenesulfonamide

MS (EI) for C₂₁H₁₅F₂N₅O₅S: 487.89 (MH+).

Example 178N-(3-(3,5-dihydroxyphenylamino)quinoxalin-2-yl)-3-nitrobenzenesulfonamide

MS (EI) for C₂₀H₁₅N₅O₆S: 453.96 (MH+).

Example 179N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)naphthalene-2-sulfonamide

MS (EI) for C₂₆H₂₂N₄O₄S: 487.0 (MH+).

Example 180N-(3-(2,5-dimethoxyphenylamino)-6,7-dimethylquinoxalin-2-yl)benzenesulfonamide

MS (EI) for C₂₄H₂₄N₄O₄S: 465.3 (MH+).

Example 1812-amino-N-(3-(N-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)-4-methylphenyl)-2-methylpropanamide

MS (EI) for C₂₆H₂₇ClN₆O₄S: 556.12 (MH+).

Example 182N-(3-(N-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(dimethylamino)acetamide

MS (EI) for C₂₅H₂₅ClN₆O₄S: 542.05 (MH+).

Example 1832-amino-N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide

MS (EI) for C₂₄H₂₄N₆O₅S: 509.59 (MH+).

Example 1843-amino-N-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2-yl)benzenesulfonamide

MS (EI) for C₂₁H₁₈ClN₅O₃S: 457.02 (MH+).

Example 1853-amino-N-(2-(3,5-dimethoxy-phenylamino)pyrido[2,3-b]pyrazin-3-yl)benzenesulfonamide

MS (EI) for C₂₁H₂₀N₆O₄S: 453.62 (MH+).

Example 186N-(3-{[(2-{[3,5-bis(methyloxy)phenyl]amino}pyrido[2,3-b]pyrazin-3-yl)amino]sulfonyl}phenyl)-N-2-[2-(dimethylamino)ethyl]-N-2-methylglycinamide

To a THF suspension (1.3 mL) of3-amino-N-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide(126 mg, 0.28 mmol) was added 0.143 mL of 2M aqueous Na₂CO₃. To thisyellow suspension is added dropwise 33 uL (0.42 mmol) of chloroacetylchloride. The reaction mixture turns clear after a few minutes and isallowed to stir at 23° C. for 1 h. To the reaction is added a DMSO (1mL) solution containing 180 uL (1.4 mmol) of N,N′,N′trimethylethelyenediamine. The reaction is then warmed to 60° C. andstirred for 18 h. The product is isolated by preparative RP-HPLC(NH₄OAc/ACN) gradient, the appropriate fractions were pooled andlyophilize to give a solid yellow as the acetic acid salt: 59 mg (51%).¹H-NMR (400 MHz, CDCL₃): δ10.1 (br s, 1), 8.37 (br s, 2), 8.18 (d, 1),7.97 (d, 1), 7.60 (br d, 1), 7.27 (s, 2), 7.20 (br s, 3), 6.15 (s, 1),3.82 (m, 2), 3.65 (s, 6), 3.20 (br m, 2), 2.82 (br s, 8), 2.42 (s, 3),2.02 (s, 3). MS (EI) for C₂₈H₃₄N₈O₅S: 595.84 (MH+).

The following title compounds were prepared according to the aboveExamples.

Example 187N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)-3-ureidobenzenesulfonamide

MS (EI) for C₂₃H₂₂N₆O₅S: 495.40 (MH+).

Example 1883-amino-N-(3-(5-methoxy-2-methyl-phenylamino)quinoxalin-2-yl)benzenesulfonamide

MS (EI) for C₂₂H₂₁N₅O₃S: 436.32 (MH+).

Example 1892-(dimethylamino)-N-(3-(N-(3-(5-methoxy-2-methylphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide

MS (EI) for C₂₆H₂₈N₆O₄S: 521.69 (MH+).

Example 190N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(4-methylpiperazin-1-yl)acetamide

MS (EI) for C₂₉H₃₃N₇O₅S: 592.61 (MH+).

Example 1912-acetamido-N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide

MS (EI) for C₂₆H₂₆N₆O₆S: 550.59 (MH+).

Example 192 tert-butyl2-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenylamino)-2-oxoethylcarbamate

MS (EI) for C₂₉H₃₂N₆O₇S: 609.32 (MH+).

Example 1933-amino-N-(3-{[3,5-bis(methyloxy)phenyl]amino}pyrido[2,3-b]pyrazin-2-yl)benzenesulfonamide

To a 1:1 THF/EtOH suspension (1 mL) of3-nitro-N-(3-{[3,5-bis(methyloxy)phenyl]amino}pyrido[2,3-b]pyrazin-2-yl)benzenesulfonamide(100 mg, 0.21 mmol) was added 46 uL (0.63 mmol) of formic acid plus 100mg (0.63 mmol) of potassium formate and 100 mg of 10% palladium oncharcoal. After refluxing the reaction for 1 h, hot filtration throughcelite, and concentration, the product is isolated by preparativeRP-HPLC (NH₄OAc/ACN) gradient. The appropriate fractions were pooled andlyophilize to give solid yellow product: 3.2 mg (4%). ¹H-NMR (400 MHz,CDCl₃): δ 8.62 (d, 1), 8.52 (s, 1), 7.62 (d, 1), 7.3 (m, 4), 7.18 (d,2), 6.88 (d, 1), 6.27 (t, 1), 3.96 (br s, 2), 3.83 (s, 6). MS (EI) forC₂₁H₂₀N₆O₄S: 453.22 (MH+).

The following title compounds were prepared according to the aboveExamples.

Example 1943-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)-N-(2-methyl-1-(piperidin-1-yl)propan-2-yl)benzamide

MS (EI) for C₃₁H₃₅ClN₆O₄S: 623.06 (MH+).

Example 1953-(N-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)-N-(2-methyl-1-oxo-1-(piperidin-1-yl)propan-2-yl)benzamide

MS (EI) for C₃₁H₃₃ClN₆O₅S: 637.65 (MH+).

Example 196N-(2-(3,5-dimethoxyphenylamino)pyrido[2,3-b]pyrazin-3-yl)-3-nitrobenzenesulfonamide

MS (EI) for C₂₁H₁₈N₆O₆S: 483.78 (MH+).

Example 197N-(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-(1-{[2-(dimethylamino)ethyl]amino}ethyl)benzenesulfonamidetrifluoroacetic acid salt

To a dichloroethane solution (0.6 mL) of3-acetyl-N-(3-{[2-chloro-5-(methyloxy)-phenyl]amino}quinoxalin-2-yl)benzenesulfonamide(150 mg, 0.31 mmol) and 51 uL (0.37 mmol) ofN,N-dimethylethelyenediamine was added 19 uL of acetic acid followed by132 mg (0.62 mmol) of sodium cyanoborohydride. The reaction mixture wasrefluxed for 18 h under a nitrogen atmosphere. After concentration (invacuo), the product is isolated by preparative RP-HPLC (0.1% TFA/ACN)gradient, followed by lyophilization of appropriate fractions to givesolid yellow solid: 189 mg (90%). ¹H-NMR (400 MHz, d₃-MeOD): δ 8.74 (s,1), 8.18 (s, 1), 8.12 (d, 1), 7.71 (m, 3), 7.48 (m, 4), 7.28 (d, 1),6.63 (d, 1), 4.38 (q, 1), 3.80 (s, 3), 3.30 (m, 3), 3.12 (m, 1), 2.84(s, 3), 1.60 (d, 3). MS (EI) for C₂₇H₃₁ClN₆O₃S: 555.56 (MH+).

Example 198N,N-{[(3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-4-methylphenyl)amino](dimethylamino)methylidene}-N-methylmethanaminium

To a dimethylformamide solution (1 mL) of3-amino-N-(3-{[2-chloro-5-(methyloxy)-phenyl]amino}quinoxalin-2-yl)-2-methylbenzenesulfonamide(200 mg, 0.40 mmol) is added 312 uL (1.8 mmol) of hunigs base and 122 mg(0.6 mmol) of HATU. After stirring for 18 h at 60° C., the product wasprecipitated from a 1:1 mixture of hexane/ethyl acetate, filtered anddried to afford 60 mg (26%). ¹H NMR (400 MHz, d₆-DMSO): δ 9.26 (b rs,1), 8.96 (br s, 1), 7.80 (s, 1), 7.51 (br s, 1), 7.45 (d, 1), 7.18 (brm,4), 6.91 (br s, 1), 6.60 (br d, 1), 3.82 (s, 3), 3.36 (s, 3), 2.85 (s,6), 2.58 (s, 3). MS (EI) for C₂₇H₃₁ClN₇O₃S+: 569.32 (MH+).

The following title compounds were prepared according to the aboveExamples.

Example 1993-acetyl-N-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2-yl)benzenesulfonamide

MS (EI) for C₂₃H₁₉ClN₄O₄S: 483.08 (MH+).

Example 200N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)benzenesulfonamide

MS (EI) for C₂₂H₂₀N₄O₄S: 437.49 (MH+).

Example 201N-(3-(5-methoxy-2-methyl-phenylamino)quinoxalin-2-yl)benzenesulfonamide

MS (EI) for C₂₂H₂₀N₄O₃S: 421.46 (MH+).

Example 202N-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2-yl)benzenesulfonamide

MS (EI) for C₂₁H₁₇ClN₄O₃S: 440.59 (MH+).

Example 203N-(3-(2,5-dimethoxyphenylamino)quinoxalin-2-yl)benzenesulfonamide

MS (EI) for C₂₂H₂₀N₄O₄S: 437.53 (MH+).

Example 2044-chloro-N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)benzenesulfonamide

MS (EI) for C₂₂H₁₉ClN₄O₄S: 470.54 (MH+).

Example 205N-(3-(5-methoxy-2-methyl-phenylamino)quinoxalin-2-yl)-3-nitrobenzenesulfonamide

MS (EI) for C₂₂H₁₉N₅O₅S: 466.32 (MH+).

Example 206N-(3-(2-chloro-5-methoxy-phenylamino)quinoxalin-2-yl)-3-nitrobenzenesulfonamide

MS (EI) for C₂₁H₁₆ClN₅O₅S: 485.86 (MH+).

Example 207N-(3-(2-chloro-5-(difluoromethoxy)-phenylamino)quinoxalin-2-yl)-3-nitrobenzenesulfonamide

MS (EI) for C₂₁H₁₄ClF₂N₅O₅S: 521.92 (MH+).

Example 208N-(3-(4-chloro-2,5-dimethoxy-phenylamino)quinoxalin-2-yl)benzenesulfonamide

MS (EI) for C₂₂H₁₉ClN₄O₄S: 470.99 (MH+).

Example 209N-(3-(4-morpholinophenylamino)quinoxalin-2-yl)benzenesulfonamide

MS (EI) for C₂₄H₂₃N₅O₃S: 461.54 (MH+).

Example 2103-amino-N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)benzenesulfonamide

N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)-3-nitrobenzenesulfonamide.A flask was charged withN-(3-chloroquinoxalin-2-yl)-3-nitrobenzenesulfonamide (5 g, 13.7 mmol),3,5-dimethoxyaniline (4.2 g, 27.4 mmol), and 80 mL of Xylene. Thereaction mixture was stirred under an N₂ atmosphere at 150° C. for 3hours, after which time, solvent was removed on a rotary evaporator, and10 mL of Dichloromethane and 50 mL of Methanol were added. The slurrywas heated to reflux and filtered while hot, resulting in 4.6 g (69.7%)ofN-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)-3-nitrobenzenesulfonamideMS (EI) for C₂₂H₁₉N₅O₆S: 482.2 (MH+).

Example 211

3-amino-N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)benzenesulfonamideA flask was charged withN-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)-3-nitrobenzenesulfonamide(3.4 g, 7.06 mmol), tin chloride hydrate (6.4 g, 28.2 mmol), and 30 mLof DMA. A few drops of water were added and the reaction mixture wasstirred at 80° C. for 3 hours, after which time, solvent was removed ona rotary evaporator, and 50 mL of water and 10 mL of Methanol wereadded. The slurry was filtered, and the filtrate was washed with MeOH,water, and diethyl ether (20 mL of each), resulting in 3.25 g3-amino-N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)benzenesulfonamide.MS (EI) for C₂₂H₂₁N₅O₄S: 461.5 (MH+).

General Library Alkylation Procedure 1

Into a 2-dram vial was placed2-bromo-N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide(86 mg, 0.15 mmol) along with 2 mL of acetonitrile. Eight equivalents(1.2 mmol) of the desired amine, aniline, hydrazine or alkoxylamine wereadded followed by the addition of Hunig's Base (41 μL, 0.25 mmol). Thereaction then was stirred at 50° C. for one hour (overnight for anilinereagents). Preparative reverse-phase HPLC was used to isolate thedesired product directly from the crude reaction mixture. A WatersFractionlynx preparative reverse-phase HPLC; equipped with a WatersSunFire Prep C18, OCD 5 μM, 30×70 mm column and running a 5-100%gradient with a binary solvent system of 25 mM ammonium acetate inwater/acetonitrile; was used to carry out the purification.

The following title compounds were prepared according to General LibraryAlkylation Procedure 1

Example 212N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(methylamino)acetamide

¹H-NMR (400 MHz, d₆-DMSO): 8.81 (s, 1H), 8.23 (t, 1H), 7.75 (d, 1H),7.66 (d, 1H), 7.41-7.38 (m, 1H), 7.35 (m, 1H), 7.32 (d, 2H), 7.29-7.27(m, 1H), 7.14-7.11 (m, 2H), 6.14 (t, 1H), 3.80 (s, 1H), 3.78 (s, 6H),2.58 (s, 3H), 1.91 (s, 2H); MS (EI) C₂₅H₂₆N₆O₅S: 523.6 (MH⁺).

Example 2132-(cyclopropylmethylamino)-N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide

¹H-NMR (400 MHz, d₆-DMSO): 10.58 (s, 1H), 8.81 (s, 1H), 8.20 (t, 1H),7.76 (d, 1H), 7.67 (d, 1H), 7.42-7.36 (m, 2H), 7.32 (d, 2H), 7.27 (s,1H), 7.14-7.12 (m, 2H), 6.15 (t, 1H), 3.93 (s, 2H), 3.78 (s, 6H), 2.89(s, 1H), 2.88 (s, 1H), 1.05-1.00 (m, 1H), 0.59 (d, 1H), 0.57 (d, 1H),0.35 (d, 1H), 0.34 (d, 1H); MS (EI) C₂₈H₃₀N₆O₅S: 563.6 (MH⁺).

Example 214N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(2-hydroxypropylamino)acetamide

¹H-NMR (400 MHz, d₆-DMSO): 10.49 ppm (s, 1H), 8.81 ppm (s, 1H), 8.23 ppm(t, 1H), 8.13 ppm (s, 1H), 7.76 ppm (d, 1H), 7.765-7.763 (dd, 1H),7.41-7.37 ppm (m, 2H), 7.33-7.32 ppm (d, 1H), 7.30-7.28 ppm (m, 1H),7.16-7.09 ppm (m, 2H), 6.55 ppm (s, 1H), 6.14 ppm (t, 1H), 5.49 ppm (d,2H), 5.25 ppm (s, 1H), 3.85 ppm (s, 1H), 3.78 ppm (s, 6H) 3.67-3.59 ppm(m, 1H), 3.00-2.89 ppm (dd, 1H), 2.79-2.76 ppm ( m, 1H), 1.10 ppm (d,1H), 1.01-0.99 ppm (d, 1H); MS (EI) C₂₇H₃₀N₆O₆S: 566.6 (MH⁺).

Example 215N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(3-fluorobenzylamino)acetamide

¹H-NMR (400 MHz, d₆-DMSO): 10.42 ppm (s, 1H), 8.82 ppm (s, 1H), 8.23 ppm(s, 1H), 8.14 ppm (s, 1H), 7.75 ppm (d, 1H), 7.65 ppm (d, 1H), 7.49-7.32ppm (m, 6H), 7.25-7.20 ppm (m, 1H), 7.14-7.12 ppm (m, 2H), 6.55 ppm (s,1H), 6.15 ppm (t, 1H), 4.14 ppm (s, 2H), 3.78 ppm (s, 6H), 3.74 ppm (s,2H); MS (EI) C₃₁H₂₉FN₆O₅S: 616.7 (MH⁺).

Example 2162-(benzylamino)-N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide

MS (EI) C₃₁H₃₀N₆O₅S: 599 (MH⁺).

Example 2172-(diethylamino)-N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide

MS (EI) C₂₈H₃₂N₆O₅S: 565 (MH⁺).

Example 2182-(4-(3,4-dichlorophenyl)piperazin-1-yl)-N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide

MS (EI) C₃₄H₃₃Cl₂N₇O₅S: 722 (MH⁺).

Example 219N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(2,2-dimethylhydrazinyl)acetamide

MS (EI) C₂₆H₂₉N₇O₅S: 552 (MH⁺).

Example 220N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(p-tolylamino)acetamide

MS (EI) C₃₁H₃₀N₆O₅S: 599 (MH⁺).

Example 2212-(benzyloxyamino)-N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide

MS (EI) C₃₁H₃₀N₆O₆S: 615 (MH⁺).

Example 2222-(2-chlorophenylamino)-N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide

MS (EI) C₃₀H₂₇ClN₆O₅S: 619 (MH⁺).

Example 223N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(isopropylamino)acetamide

MS (EI) C₂₇H₃₀N₆O₅S: 551 (MH⁺).

Example 2242-(4-cyclopentylpiperazin-1-yl)-N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide

MS (EI) C₃₃H₃₉N₇O₅S: 646 (MH⁺).

Example 225N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(4-propylpiperidin-1-yl)acetamide

MS (EI) C₃₂H₃₈N₆O₅S: 619 (MH⁺).

Example 226N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(isobutoxyamino)acetamide

MS (EI) C₂₈H₃₂N₆O₆S: 581 (MH⁺).

Example 2272-(3-tert-butylphenylamino)-N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide

MS (EI) C₃₄H₃₆N₆O₅S: 641 (MH⁺).

Example 228N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(2-phenylpropan-2-ylamino)acetamide

MS (EI) C₃₃H₃₄N₆O₅S: 627 (MH⁺).

Example 229N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(3-fluoro-4-hydroxyphenylamino)acetamide

MS (EI) C₃₀H₂₇FN₆O₆S: 619 (MH⁺).

Example 230N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(2-(methylthio)benzylamino)acetamide

MS (EI) C₃₂H₃₂N₆O₅S₂: 645 (MH⁺).

Example 231N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(5-fluoro-2-methylbenzylamino)acetamide

MS (EI) C₃₂H₃₁FN₆O₅S: 631 (MH⁺).

Example 232N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(2-phenylpyrrolidin-1-yl)acetamide

MS (EI) C₃₄H₃₄N₆O₅S: 639 (MH⁺).

Example 2332-(2-benzylpyrrolidin-1-yl)-N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide

MS (EI) C₃₅H₃₆N₆O₅S: 653 (MH⁺).

Example 234N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(2-phenylmorpholino)acetamide

MS (EI) C₃₄H₃₄N₆O₆S: 655 (MH⁺).

Example 235N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(2-(pyridin-4-yl)piperidin-1-yl)acetamide

MS (EI) C₃₄H₃₅N₇O₅S: 654 (MH⁺).

Example 236N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(o-tolylamino)acetamide

MS (EI) C₃₁H₃₀N₆O₅S: 599 (MH⁺).

Example 237N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(2,4-dimethylbenzylamino)acetamide

MS (EI) C₃₃H₃₄N₆O₅S: 627 (MH⁺).

Example 238N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(methyl(pyridin-3-ylmethyl)amino)acetamide

MS (EI) C₃₁H₃₁N₇O₅S: 614 (MH⁺).

Example 2392-(3-chloro-4-methylbenzylamino)-N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide

MS (EI) C₃₂H₃₁ClN₆O₅S: 647 (MH⁺).

Example 240N-(3-(N-(3-(3,5-dimethoxy-phenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-((2-(dimethylamino)-ethyl)(methyl)amino)acetamide

MS (EI) C₂₉H₃₅N₇O₅S: 594 (MH⁺).

Example 2412-(4-acetylpiperazin-1-yl)-N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide

MS (EI) C₃₀H₃₃N₇O₆S: 620 (MH⁺).

Example 242N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(methyl(1-methylpyrrolidin-3-yl)amino)acetamide

MS (EI) C₃₀H₃₅N₇O₅S: 606 (MH⁺).

Example 243N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(4-methyl-1,4-diazepan-1-yl)acetamide

MS (EI) C₃₀H₃₅N₇O₅S: 606 (MH⁺).

Example 2442-(4-allylpiperazin-1-yl)-N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide

MS (EI) C₃₁H₃₅N₇O₅S: 618 (MH⁺).

Example 245N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(4-isopropylpiperazin-1-yl)acetamide

MS (EI) C₃₁H₃₇N₇O₅S: 620 (MH⁺).

Example 246N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(3-(dimethylamino)pyrrolidin-1-yl)acetamide

MS (EI) C₃₀H₃₅N₇O₅S: 606 (MH⁺).

Example 247N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(3-(dimethylamino)azetidin-1-yl)acetamide

MS (EI) C₂₉H₃₃N₇O₅S: 592 (MH⁺).

Example 248N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(4-oxopiperidin-1-yl)acetamide

MS (EI) C₂₉H₃₀N₆O₆S: 591 (MH⁺).

Example 249N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-((2-methoxyethyl)(methyl)amino)acetamide

MS (EI) C₂₈H₃₂N₆O₆S: 581 (MH⁺).

Example 250N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(4-methylbenzyloxyamino)acetamide

MS (EI) C₃₂H₃₂N₆O₆S: 629 (MH⁺).

Example 251N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(2-methoxybenzyloxyamino)acetamide

MS (EI) C₃₂H₃₂N₆O₇S: 645 (MH⁺).

Example 252N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(propylamino)acetamide

MS (EI) C₂₇H₃₀N₆O₅S: 551 (MH⁺).

Example 253N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(ethyl(methyl)amino)acetamide

MS (EI) C₂₇H₃₀N₆O₅S: 551 (MH⁺).

Example 2542-(allyl(methyl)amino)-N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide

MS (EI) C₂₈H₃₀N₆O₅S: 563 (MH⁺).

Example 2552-(tert-butylamino)-N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide

MS (EI) C₂₈H₃₂N₆O₅S: 565 (MH⁺).

Example 256N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(isobutylamino)acetamide

MS (EI) C₂₈H₃₂N₆O₅S: 565 (MH⁺).

Example 2572-(butylamino)-N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide

MS (EI) C₂₈H₃₂N₆O₅S: 565 (MH⁺).

Example 258N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(isopropyl(methyl)amino)acetamide

MS (EI) C₂₈H₃₂N₆O₅S: 565 (MH⁺).

Example 259N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(4-formylpiperazin-1-yl)acetamide

MS (EI) C₂₉H₃₁N₇O₆S: 606 (MH⁺).

Example 260N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(4-ethylpiperazin-1-yl)acetamide

MS (EI) C₃₀H₃₅N₇O₅S: 606 (MH⁺).

Example 261N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(4-formyl-1,4-diazepan-1-yl)acetamide

MS (EI) C₃₀H₃₃N₇O₆S: 620 (MH⁺).

Example 262N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(ethyl(2-hydroxyethyl)amino)acetamide

MS (EI) C₂₈H₃₂N₆O₆S: 581 (MH⁺).

Example 263(S)-N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(3-hydroxypyrrolidin-1-yl)acetamide

MS (EI) C₂₈H₃₀N₆O₆S: 579 (MH⁺).

Example 264N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(2,6-dimethylmorpholino)acetamide

MS (EI) C₃₀H₃₄N₆O₆S: 607 (MH⁺).

Example 265N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(2-methylbenzylamino)acetamide

MS (EI) C₃₂H₃₂N₆O₅S: 613 (MH⁺).

Example 266N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(2-methoxyethylamino)acetamide

MS (EI) C₂₇H₃₀N₆O₆S: 567 (MH⁺).

Example 267N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(thiazolidin-3-yl)acetamide

MS (EI) C₂₇H₂₈N₆O₅S₂: 581 (MH⁺).

Example 268N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(3-(hydroxymethyl)piperidin-1-yl)acetamide

MS (EI) C₃₀H₃₄N₆O₆S: 607 (MH⁺).

Example 268N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(2-phenylpropylamino)acetamide

MS (EI) C₃₃H₃₄N₆O₅S: 627 (MH⁺).

Example 269N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(isobutyl(methyl)amino)acetamide

MS (EI) C₂₉H₃₄N₆O₅S: 579 (MH⁺).

Example 270N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(phenylamino)acetamide

MS (EI) C₃₀H₂₈N₆O₅S: 585 (MH⁺).

Example 271N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(2-propylphenylamino)acetamide

MS (EI) C₃₃H₃₄N₆O₅S: 627 (MH⁺).

Example 272N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(2-isopropylphenylamino)acetamide

MS (EI) C₃₃H₃₄N₆O₅S: 627 (MH⁺).

Example 273N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(2-fluoro-4-methylphenylamino)acetamide

MS (EI) C₃₁H₂₉FN₆O₅S: 617 (MH⁺).

Example 2742-(4-chlorophenylamino)-N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide

MS (EI) C₃₀H₂₇ClN₆O₅S: 619 (MH⁺).

Example 275N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(2-methoxyphenylamino)acetamide

MS (EI) C₃₁H₃₀N₆O₆S: 615 (MH⁺).

Example 2762-(3-chlorophenylamino)-N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide

MS (EI) C₃₀H₂₇ClN₆O₅S: 619 (MH⁺).

Example 277N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(2,3-dimethylphenylamino)acetamide

MS (EI) C₃₂H₃₂N₆O₅S: 613 (MH⁺).

Example 278N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(2-fluorophenylamino)acetamide

MS (EI) C₃₀H₂₇FN₆O₅S: 603 (MH⁺).

Example 279N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(3-fluorophenylamino)acetamide

MS (EI) C₃₀H₂₇FN₆O₅S: 603 (MH⁺).

Example 280N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(thiophen-2-ylmethylamino)acetamide

MS (EI) C₂₉H₂₈N₆O₅S₂: 605 (MH⁺).

Example 2812-(cyclohexyl(ethyl)amino)-N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide

MS (EI) C₃₂H₃₈N₆O₅S: 619 (MH⁺).

Example 2822-((cyclopropylmethyl)(propyl)amino)-N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide

MS (EI) C₃₁H₃₆N₆O₅S: 605 (MH⁺).

Example 2832-(allyl(cyclopentyl)amino)-N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide

MS (EI) C₃₂H₃₆N₆O₅S: 617 (MH⁺).

Example 284N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(ethyl(isopropyl)amino)acetamide

MS (EI) C₂₉H₃₄N₆O₅S: 579 (MH⁺).

Example 285N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(ethyl(phenyl)amino)acetamide

MS (EI) C₃₂H₃₂N₆O₅S: 613 (MH⁺).

Example 286N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(2-methylpyrrolidin-1-yl)acetamide

MS (EI) C₂₉H₃₂N₆O₅S: 577 (MH⁺).

Example 287N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(2-methylpiperidin-1-yl)acetamide

MS (EI) C₃₀H₃₄N₆O₅S: 591 (MH⁺).

Example 288N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(pyridin-2-ylmethylamino)acetamide

MS (EI) C₃₀H₂₉N₇O₅S: 600 (MH⁺).

Example 2892-(benzyl(methyl)amino)-N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide

MS (EI) C₃₂H₃₂N₆O₅S: 613 (MH⁺).

Example 290N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(1-phenylethylamino)acetamide

MS (EI) C₃₂H₃₂N₆O₅S: 613 (MH⁺).

Example 291N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(3-methylpiperidin-1-yl)acetamide

MS (EI) C₃₀H₃₄N₆O₅S: 591 (MH⁺).

Example 292N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(4-methylpiperidin-1-yl)acetamide

MS (EI) C₃₀H₃₄N₆O₅S: 591 (MH⁺).

Example 2932-(3,4-dihydroisoquinolin-2(1H)-yl)-N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide

MS (EI) C₃₃H₃₂N₆O₅S: 625 (MH⁺).

Example 294N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(2,6-dimethylpiperidin-1-yl)acetamide

MS (EI) C₃₂H₃₆N₆O₅S: 605 (MH⁺).

Example 295N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(3-hydroxybenzylamino)acetamide

MS (EI) C₃₁H₃₀N₆O₆S: 615 (MH⁺).

General Library Acylation Procedure 2

Into a 2-dram vial were added3-amino-N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)benzenesulfonamide(54 mg, 0.12 mmol), DMA ( )2 mL) and the desired carboxylic acid (0.17mmol). Hunig's Base (70 □L, 0.4 mmol) followed by HATU (53 mg, 0.14mmol) were added to the vial and the reaction mixture stirred at 50° C.overnight. Preparative reverse-phase HPLC was used to isolate thedesired product directly from the crude reaction mixture. A WatersFractionlynx preparative reverse-phase HPLC; equipped with a WatersSunFire Prep C18, OCD 5 □M, 30×70 mm column and running a 5-100%gradient with a binary solvent system of 25 mM ammonium acetate inwater/acetonitrile; was used to carry out the purification.

The following title compounds were prepared according to General LibraryAcylation Procedure 2.

Example 296N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)propionamide

¹H-NMR (400 MHz, d₆-DMSO): 12.37 (s, 1H), 10.20 (s, 1H), 8.88 (s, 1H),8.37 (s, 1H), 7.93 (s, 1H), 7.77 (t, 2H), 7.59 (t, 1H), 7.51 (t, 1H),7.41-7.34 (m, 4H), 6.24 (t, 1H), 3.76 (s, 6H), 2.36-2.31 (dd, 2H), 1.10(s, 1H), 1.08 (s, 1H), 1.06 (s, 1H); MS (EI) C₂₅H₂₅N₅0₅S: 508.6 (MH⁺).

Example 297N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)pyridazine-4-carboxamide

¹H-NMR (400 MHz, d₆-DMSO): 11.01 (s, 1H), 9.66 (dd, 1H), 9.52 (dd, 1H),8.90 (s, 1H), 8.55 (s, 1H), 8.13 (dd, 1H), 7.99 (d, 1H), 7.93 (d, 1H),7.65-7.58 (m, 2H), 7.42-7.35 (m, 4H), 6.24 (t, 1H), 3.75 (s, 6H); MS(EI) C₂₇H₂₃N₇0₅S: 558.6 (MH⁺).

Example 298N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-methylnicotinamide

¹H-NMR (400 MHz, d₆-DMSO): 10.78 ppm (s, 1H), 8.90 ppm (s, 1H),8.58-8.57 ppm (dd, 2H), 7.90-7.86 (m, 4H), 7.60-7.56 ppm (m, 2H),7.42-7.34 (m, 5H), 6.23 ppm (t, 1H), 3.74 ppm (s, 6H), 2.57 ppm (s, 3H);MS (EI) C₂₉H₂₆N₅O₅S: 570.6 (MH⁺).

Example 299N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(o-tolyloxy)acetamide

¹H-NMR (400 MHz, d₆-DMSO): 12.37 ppm (s, 1H), 10.41 ppm (s, 1H), 8.90ppm (s, 1H), 8.41 ppm (s, 1H), 7.93 ppm (s, 1H), 7.90-7.8 (m, 2H),7.59-7.53 ppm (m, 2H), 7.42-7.33 ppm (m, 4H), 7.17-7.12 ppm (m, 2H),6.89-6.85 ppm (m, 2H), 6.24 ppm (t, 1H), 4.74 ppm (s, 2H), 3.76 ppm (s,6H), 2.33 ppm (s, 2H); MS (EI) C₃₁H₂₉N₅O₆S: 599.7 (MH⁺).

Example 300N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-methoxy-4-methylbenzamide

MS (EI) C₃₁H₂₉N₅O₆S: 600 (MH⁺).

Example 301N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-methoxy-4-methylbenzamide

MS (EI) C₂₈H₂₄N₆O₅S: 557 (MH⁺).

Example 302N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)thiazole-4-carboxamide

MS (EI) C₂₆H₂₂N₆O₅S₂: 563 (MH⁺).

Example 3032-bromo-N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)thiophene-3-carboxamide

MS (EI) C₂₇H₂₂BrN₅O₅S₂ 640 (MH⁺).

Example 304N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)pivalamide

MS (EI) C₂₇H₂₉N₅O₅S: 536 (MH⁺).

Example 305N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)pent-4-enamide

MS (EI) C₂₇H₂₇N₅O₅S: 534 (MH⁺).

Example 306N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)benzamide

MS (EI) C₂₉H₂₅N₅O₅S: 556 (MH⁺).

Example 307N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)butyramide

MS (EI) C₂₆H₂₇N₅O₅S: 522 (MH⁺).

Example 308N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-methoxyacetamide

MS (EI) C₂₅H₂₅N₅O₆S: 524 (MH⁺).

Example 309N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)cyclobutanecarboxamide

MS (EI) C₂₇H₂₇N₅O₅S: 534 (MH⁺).

Example 310N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-methylcyclopropanecarboxamide

MS (EI) C₂₇H₂₇N₅O₅S: 534 (MH⁺).

Example 311N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-1-methylcyclopropanecarboxamide

MS (EI) C₂₇H₂₇N₅O₅S: 534 (MH⁺).

Example 312N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-methylbutanamide

MS (EI) C₂₇H₂₉N₅O₅S: 536 (MH⁺).

Example 313N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-ethoxyacetamide

MS (EI) C₂₆H₂₇N₅O₆S: 538 (MH⁺).

Example 314N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-methoxypropanamide

MS (EI) C₂₆H₂₇N₅O₆S: 538 (MH⁺).

Example 315N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-hydroxyacetamide

MS (EI) C₂₄H₂₃N₅O₆S: 510 (MH⁺).

Example 316N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)isobutyramide

MS (EI) C₂₆H₂₇N₅O₅S: 522 (MH⁺).

Example 317N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-1-hydroxycyclopropanecarboxamide

MS (EI) C₂₆H₂₅N₅O₆S: 536 (MH⁺).

Example 318N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)furan-3-carboxamide

MS (EI) C₂₇H₂₃N₅O₆S: 546 (MH⁺).

Example 319N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)tetrahydrofuran-3-carboxamide

MS (EI) C₂₇H₂₇N₅O₆S: 550 (MH⁺).

Example 320N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)tetrahydrofuran-2-carboxamide

MS (EI) C₂₇H₂₇N₅O₆S: 550 (MH⁺).

Example 321N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)furan-2-carboxamide

MS (EI) C₂₇H₂₃N₅O₆S: 546 (MH⁺).

Example 322N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)isonicotinamide

MS (EI) C₂₈H₂₄N₆O₅S: 557 (MH⁺).

Example 323N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-1H-pyrrole-2-carboxamide

MS (EI) C₂₇H₂₄N₆O₅S: 545 (MH⁺).

Example 324N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)pyrazine-2-carboxamide

MS (EI) C₂₇H₂₃N₇O₅S: 558 (MH⁺).

Example 325N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-1-methyl-1H-pyrrole-2-carboxamide

MS (EI) C₂₈H₂₆N₆O₅S: 559 (MH⁺).

Example 326N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-5-methylisoxazole-3-carboxamide

MS (EI) C₂₇H₂₄N₆O₆S: 561 (MH⁺).

Example 327N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)thiophene-2-carboxamide

MS (EI) C₂₇H₂₃N₅O₅S₂: 562 (MH⁺).

Example 328(S)-N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-1-methylpyrrolidine-2-carboxamide

MS (EI) C₂₈H₃₀N₆O₅S: 563 (MH⁺).

Example 329N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-methylbenzamide

MS (EI) C₃₀H₂₇N₅O₅S: 570 (MH⁺).

Example 330N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-phenylacetamide

MS (EI) C₃₀H₂₇N₅O₅S: 570 (MH⁺).

Example 331N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-methylpicolinamide

MS (EI) C₂₉H₂₆N₆O₅S: 571 (MH⁺).

Example 332N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(pyridin-3-yl)acetamide

MS (EI) C₂₉H₂₆N₆O₅S: 571 (MH⁺).

Example 333N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-6-hydroxypicolinamide

MS (EI) C₂₈H₂₄N₆O₆S: 573 (MH⁺).

Example 334N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-fluorobenzamide

MS (EI) C₂₉H₂₄FN₅O₅S: 574 (MH⁺).

Example 335N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-4-fluorobenzamide

MS (EI) C₂₉H₂₄FN₅O₅S: 574 (MH⁺).

Example 336N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-fluorobenzamide

MS (EI) C₂₉H₂₄FN₅O₅S: 574 (MH⁺).

Example 3372-cyclohexyl-N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide

MS (EI) C₃₀H₃₃N₅O₅S: 576 (MH⁺).

Example 338N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(2-oxocyclopentyl)acetamide

MS (EI) C₂₉H₂₉N₅O₆S: 576 (MH⁺).

Example 3394-cyclopropyl-N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-4-oxobutanamide

MS (EI) C₂₉H₂₉N₅O₆S: 576 (MH⁺).

Example 340N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-oxocyclohexanecarboxamide

MS (EI) C₂₉H₂₉N₅O₆S: 576 (MH⁺).

Example 341N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-(pyridin-3-yl)propanamide

MS (EI) C₃₀H₂₈N₆O₅S: 585 (MH⁺).

Example 342N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-methoxybenzamide

MS (EI) C₃₀H₂₇N₅O₆S: 586 (MH⁺).

Example 343N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-methoxybenzamide

MS (EI) C₃₀H₂₇N₅O₆S: 586 (MH⁺).

Example 344N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-phenoxyacetamide

MS (EI) C₃₀H₂₇N₅O₆S: 586 (MH⁺).

Example 345N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-4-methoxybenzamide

MS (EI) C₃₀H₂₇N₅O₆S: 586 (MH⁺).

Example 346N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(4-fluorophenyl)acetamide

MS (EI) C₃₀H₂₆FN₅O₅S: 588 (MH⁺).

Example 347N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(2-fluorophenyl)acetamide

MS (EI) C₃₀H₂₆FN₅O₅S: 588 (MH⁺).

Example 348N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(3-fluorophenyl)acetamide

MS (EI) C₃₀H₂₆FN₅O₅S: 588 (MH⁺).

Example 3492-chloro-N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)benzamide

MS (EI) C₂₉H₂₄ClN₅O₅S: 590 (MH⁺).

Example 3504-chloro-N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)benzamide

MS (EI) C₂₉H₂₄ClN₅O₅S: 590 (MH⁺).

Example 3513-chloro-N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)benzamide

MS (EI) C₂₉H₂₄ClN₅O₅S: 590 (MH⁺).

Example 352(1R,2R)-N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-phenylcyclopropanecarboxamide

MS (EI) C₃₂H₂₉N₅O₅S: 596 (MH⁺).

Example 353N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-1-phenylcyclopropanecarboxamide

MS (EI) C₃₂H₂₉N₅O₅S: 596 (MH⁺).

Example 354N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(1H-imidazol-4-yl)acetamide

MS (EI) C₂₇H₂₅N₇O₅S: 560 (MH⁺).

Example 355N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-4-methoxy-2-methylbenzamide

MS (EI) C₃₁H₂₉N₅O₆S: 600 (MH⁺).

Example 356N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(4-fluorophenoxy)acetamide

MS (EI) C₃₀H₂₆FN₅O₆S: 604 (MH⁺).

Example 357N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-5-fluoro-2-methoxybenzamide

MS (EI) C₃₀H₂₆FN₅O₆S: 604 (MH⁺).

Example 3582-(4-chlorophenyl)-N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide

MS (EI) C₃₀H₂₆ClN₅O₅S: 604 (MH⁺).

Example 3592-(2-chlorophenyl)-N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide

MS (EI) C₃₀H₂₆ClN₅O₅S: 604 (MH⁺).

Example 3602-(3-chlorophenyl)-N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide

MS (EI) C₃₀H₂₆ClN₅O₅S: 604 (MH⁺).

Example 3611-acetyl-N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)piperidine-4-carboxamide

MS (EI) C₃₀H₃₂N₆O₆S: 605 (MH⁺).

Example 362N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(pyridin-4-yl)acetamide

MS (EI) C₂₉H₂₆N₆O₅S: 571 (MH⁺).

Example 363N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(pyridin-2-yl)acetamide

MS (EI) C₂₉H₂₆N₆O₅S: 571 (MH⁺).

Example 3642,4-dichloro-N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)benzamide

MS (EI) C₂₉H₂₃Cl₂N₅O₅S: 624 (MH⁺).

Example 3653,4-dichloro-N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)benzamide

MS (EI) C₂₉H₂₃Cl₂N₅O₅S: 624 (MH⁺).

Example 3662,5-dichloro-N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)benzamide

MS (EI) C₂₉H₂₃Cl₂N₅O₅S: 624 (MH⁺).

Example 3673,5-dichloro-N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)benzamide

MS (EI) C₂₉H₂₃Cl₂N₅O₅S: 624 (MH⁺).

Example 3682,3-dichloro-N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)benzamide

MS (EI) C₂₉H₂₃Cl₂N₅O₅S: 624 (MH⁺).

Example 369N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)pentanamide

MS (EI) C₂₇H₂₉N₅O₅S: 536 (MH⁺).

Example 370N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-methylbutanamide

MS (EI) C₂₇H₂₉N₅O₅S: 536 (MH⁺).

Example 371N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-1H-imidazole-2-carboxamide

MS (EI) C₂₆H₂₃N₇O₅S: 546 (MH⁺).

Example 372N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-1H-imidazole-4-carboxamide

MS (EI) C₂₆H₂₃N₇O₅S: 546 (MH⁺).

Example 373N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)isoxazole-5-carboxamide

MS (EI) C₂₆H₂₂N₆O₆S: 547 (MH⁺).

Example 374N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-3,3-dimethylbutanamide

MS (EI) C₂₈H₃₁N₅O₅S: 550 (MH⁺).

Example 375N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-methylpentanamide

MS (EI) C₂₈H₃₁N₅O₅S: 550 (MH⁺).

Example 376N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2,2-dimethylbutanamide

MS (EI) C₂₈H₃₁N₅O₅S: 550 (MH⁺).

Example 377N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-4-methylpentanamide

MS (EI) C₂₈H₃₁N₅O₅S: 550 (MH⁺).

Example 378N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)pyrimidine-5-carboxamide

MS (EI) C₂₇H₂₃N₇O₅S: 558 (MH⁺).

Example 379N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-methylfuran-2-carboxamide

MS (EI) C₂₈H₂₅N₅O₆S: 560 (MH⁺).

Example 380N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)thiophene-3-carboxamide

MS (EI) C₂₇H₂₃N₅O₅S₂: 562 (MH⁺).

Example 381N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-oxocyclopentanecarboxamide

MS (EI) C₂₈H₂₇N₅O₆S: 562 (MH⁺).

Example 382N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(2-methoxyethoxy)acetamide

MS (EI) C₂₇H₂₉N₅O₇S: 568 (MH⁺).

Example 383N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-4-methylbenzamide

MS (EI) C₃₀H₂₇N₅O₅S: 570 (MH⁺).

Example 384N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(3-methylisoxazol-4-yl)acetamide

MS (EI) C₂₈H₂₆N₆O₆S: 575 (MH⁺).

Example 3853-cyclopentyl-N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)propanamide

MS (EI) C₃₀H₃₃N₅O₅S: 576 (MH⁺).

Example 386N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-o-tolylacetamide

MS (EI) C₃₁H₂₉N₅O₅S: 584 (MH⁺).

Example 387N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-methoxynicotinamide

MS (EI) C₂₉H₂₆N₆O₆S: 587 (MH⁺).

Example 388N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-4-fluoro-3-methylbenzamide

MS (EI) C₃₀H₂₆FN₅O₅S: 588 (MH⁺).

Example 389N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-fluoro-2-methylbenzamide

MS (EI) C₃₀H₂₆FN₅O₅S: 588 (MH⁺).

Example 390N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-fluoro-4-methylbenzamide

MS (EI) C₃₀H₂₆FN₅O₅S: 588 (MH⁺).

Example 391N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-fluoro-5-methylbenzamide

MS (EI) C₃₀H₂₆FN₅O₅S: 588 (MH⁺).

Example 392N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-5-fluoro-2-methylbenzamide

MS (EI) C₃₀H₂₆FN₅O₅S: 588 (MH⁺).

Example 3936-chloro-N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)nicotinamide

MS (EI) C₂₈H₂₃ClN₆O₅S: 591 (MH⁺).

Example 3942-chloro-N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)nicotinamide

MS (EI) C₂₈H₂₃ClN₆O₅S: 591 (MH⁺).

Example 3952-chloro-N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)isonicotinamide

MS (EI) C₂₈H₂₃ClN₆O₅S: 591 (MH⁺).

Example 396N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-4-(dimethylamino)benzamide

MS (EI) C₃₁H₃₀N₆O₅S: 599 (MH⁺).

Example 397N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-(dimethylamino)benzamide

MS (EI) C₃₁H₃₀N₆O₅S: 599 (MH⁺).

Example 398N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)benzo[d][1,3]dioxole-5-carboxamide

MS (EI) C₃₀H₂₅N₅O₇S: 600 (MH⁺).

Example 399N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(m-tolyloxy)acetamide

MS (EI) C₃₁H₂₉N₅O₆S: 600 (MH⁺).

Example 400N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(4-methoxyphenyl)acetamide

MS (EI) C₃₁H₂₉N₅O₆S: 600 (MH⁺).

Example 401N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(2-methoxyphenyl)acetamide

MS (EI) C₃₁H₂₉N₅O₆S: 600 (MH⁺).

Example 402N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(3-methoxyphenyl)acetamide

MS (EI) C₃₁H₂₉N₅O₆S: 600 (MH⁺).

Example 403N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-methoxy-4-methylbenzamide

MS (EI) C₃₁H₂₉N₅O₆S: 600 (MH⁺).

Example 404N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-fluoro-4-methoxybenzamide

MS (EI) C₃₀H₂₆FN₅O₆S: 604 (MH⁺).

Example 405N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-fluoro-6-methoxybenzamide

MS (EI) C₃₀H₂₆FN₅O₆S: 604 (MH⁺).

Example 406N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-(4-methoxyphenyl)propanamide

MS (EI) C₃₂H₃₁N₅O₆S: 614 (MH⁺).

Example 407N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-(2-methoxyphenyl)propanamide

MS (EI) C₃₂H₃₁N₅O₆S: 614 (MH⁺).

Example 408N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-(3-methoxyphenyl)propanamide

MS (EI) C₃₂H₃₁N₅O₆S: 614 (MH⁺).

General Library Acylation Procedure 2a

Into a 20 mL vial was added3-amino-N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)benzenesulfonamide(0.24 mmol, 1 equiv), DMA (5 mL) and1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (0.336 mmol, 1.4equiv). Hunig's Base (0.792 mmol, 3.3 equiv) and HATU (0.288 mmol, 1.2equiv) were added to the vial and the reaction mixture was then stirredat room temperature overnight. Completion of the reaction was indicatedby LCMS. The solvent was removed by rotary evaporation. The crudemixture was carried forward without further purification. The residuewas suspended in 5 mL ethyl acetate and chilled in an ice bath. Asolution of 4 N HCl in dioxane (3 mL, 5 equiv) was added with stirring.The reaction mixture was then stirred at room temperature overnight. Thesolid materials were collected by filtration, washed with ethylacetatethen purified further by preparative reverse-phase HPLC (ammoniumacetate/ACN). A Waters Fractionlynx preparative reverse-phase HPLC;equipped with a Waters SunFire Prep C18, OCD 5 □M, 30×70 mm column andrunning a 5-100% gradient with a binary solvent system of 25 mM ammoniumacetate in water/acetonitrile; was used to carry out the purification.

The following title compounds were prepared according to General LibraryAcylation Procedure 2a

Example 409N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)azetidine-3-carboxamide

¹H-NMR (400 MHz, d₆-DMSO): 10.26 (s, 1H), 8.81 (s, 1H), 8.25 (t, 1H),8.14 (s, 1H), 7.74 (d, 1H), 7.69 (d, 1H), 7.41-7.39 (m, 1H), 7.36 (d,1H), 7.32 (d, 2H), 7.30-7.28 (dd, 1H), 7.14-7.11 (m, 2H), 6.14 (t, 1H),4.09 (d, 4H), 3.78 (s, 6H); MS (EI) C₂₆H₂₆N₆0₅S: 535.6 (MH⁺).

Procedure 3: N-(3-chloroquinoxalin-2-yl)benzenesulfonamide

A flask was charged with 2,3-dichloroquinoxaline (3.5 g, 18 mmol), 85 mLof dimethylsulfoxide, benzene sulfonamide (2.8 g, 18 mmol), and cesiumcarbonate (5.8 g, 18 mmol). The reaction mixture was stirred under an N2atmosphere for 15 h at 150° C., after which time, it was transferred toa separatory funnel and 100 mL of water were added. Concentrated HCl wasthen added in order to acidify the reaction mixture to pH<2. The aqueouslayer was subsequently washed three times with 90 mL ethyl acetate. Theethyl acetate layers were then washed two times with 150 mL water, threetimes with 100 mL brine and then dried over sodium sulfate. The ethylacetate was removed on a rotary-evaporator. A slurry was formed byadding ethyl acetate and dichloromethane to the dried crude product,filtration yielded N-(3-chloroquinoxalin-2-yl)benzenesulfonamide whichwas submitted to the next step without further purification. MS (EI)C₁₄H₁₀ClN₃O₂S: 319.9 (MH+)⁺.

Example 410 N-(3-(4-fluorophenylamino)quinoxalin-2-yl)benzenesulfonamide

A CEM microwave reaction vessel was charged withN-(3-chloroquinoxalin-2-yl)benzenesulfonamide (52 mg, 0.16 mmol),4-fluoroaniline (36 mg, 0.32 mmol), and 0.8 mL of dimethylacetamide. Thevessel was sealed and the reaction mixture was heated under microwaveradiation for 25 m at 120° C. in a CEM Discover microwave instrument.Methanol (1 mL) was added to the reaction mixture and after 20 minutesthe product precipitated out of the solution. Filtration yielded 39 mg(62%) of N-(3-(4-fluorophenylamino)quinoxalin-2-yl)benzenesulfonamide.¹H-NMR (400 MHz, d₆-DMSO): δ 12.30 (s, 1H), 9.11 (s, 1H), 8.16-8.10 (d,2H), 8.02-7.90 (m, 3H), 7.68-7.58 (m, 3H), 7.55-7.51 (m, 1H), 7.41-7.32(m, 2H), 7.25-7.16 (m, 2H); MS (EI) C₂₀H₁₅FN₄O₂S: 395.0 (MH⁺).

Procedure 4: 2-(dimethylamino)-N-(3-sulfamoylphenyl)acetamide

A flask was charged with 3-aminobenzene sulfonamide (3.3 g, 19 mmol),and 20 mL of 1:1 acetone:H₂O. The solution was stirred at roomtemperature until the aminobenzene sulfonamide had dissolved. The flaskwas then cooled in an ice bath and dimethylamino-acetyl chloride HCl(4.6 g, 29 mmol) was added. To the resulting slurry sodium bicarbonate(4.8 g, 57 mmol) was added over a 15 m period. After 30 min the reactionwas removed from the ice bath and allowed to stir at room temperaturefor 15 h. The reaction mixture was then filtered and washed withmethanol and acetonitrile. The filtrate was dried on a rotary evaporatorto yield 2-(dimethylamino)-N-(3-sulfamoylphenyl)acetamide, which wassubmitted to the next step without further purification. MS (EI)C₁₀H₁₅N₃O₃S: 258.0 (MH+).

Example 411N-(3-(N-(3-chloroquinoxalin-2-yl)sulfamoyl)phenyl)-2-(dimethylamino)acetamide

A flask was charged with dichloroquinozaline (1.0 g, 5.8 mmol), 10 mL ofdimethylacetamide, 2-(dimethylamino)-N-(3-sulfamoylphenyl)acetamide(0.70 g, 2.7 mmol), and cesium carbonate (1.8 g, 5.5 mmol). The reactionmixture was stirred for 3 h at 140° C. and then filtered. The solventwas evaporated from the filtrate on a rotary-evaporator to yield(N-(3-(N-(3-chloroquinoxalin-2-yl)sulfamoyl)phenyl)-2-(dimethylamino)acetamide)which was submitted to the next step without further purification. MS(EI) C₁₈H₁₈ClN₅O₃S: 420.0 (MH+).

Two similar procedures were then used to conduct the general reactionshown.

A CEM microwave reaction vessel was charged withN-(3-(N-(3-chloroquinoxalin-2-yl)sulfamoyl)phenyl)-2-(dimethylamino)acetamide(30 mg, 0.071 mmol), the desired aniline (16 mg, 0.14 mmol, 2 eq), and0.5 mL of Dimethylacetamide. The vessel was sealed and the reactionmixture was heated under microwave radiation for 70 min at 140° C. in aCEM Discover microwave instrument. The solvent was then removed byrotary-evaporation. Purification of the final product was accomplishedby preparatory reverse-phase HPLC with the eluents 25 mM aqueousNH₄OAc/ACN to yield2-(dimethylamino)-N-(3-(N-(3-(3-fluorophenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide.

The following compounds were prepared according to the above Examples.

Example 4122-(dimethylamino)-N-(3-(N-(3-(3-fluorophenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide

2-(dimethylamino)-N-(3-(N-(3-(3-fluorophenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide.¹H-NMR (400 MHz, CDCl₃): 9.40 ppm (s, 1H), 8.43 ppm (s, 1H), 8.22 ppm(s, 1H), 8.07-8.02 ppm (d, 1H), 7.97-7.93 ppm (d, 1H), 7.76-7.71 (m,2H), 7.53-7.48 ppm (t, 1H), 7.45-7.36 ppm (m, 4H), 7.35-7.28 ppm (m,2H), 6.84-6.77 ppm (t, 1H), 3.10 ppm (s, 2H), 2.38 ppm (s, 6H); MS (EI)C₂₄H₂₃FN₆O₃S: 495 (MH⁺).

Example 4132-(dimethylamino)-N-(3-(N-(3-(4-fluorophenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide

MS (EI) C₂₄H₂₃FN₆O₃S: 495 (MH⁺).

Example 4142-(dimethylamino)-N-(3-(N-(3-(4-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide

MS (EI) C₂₅H₂₆N₆O₄S: 507 (MH⁺).

Example 415N-(3-(N-(3-(4-chlorophenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(dimethylamino)acetamide

MS (EI) C₂₄H₂₃ClN₆O₃S: 511 (MH⁺).

Example 416N-(3-(N-(3-(3-chlorophenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(dimethylamino)acetamide

MS (EI) C₂₄H₂₃ClN₆O₃S: 511 (MH⁺)

A CEM microwave reaction vessel was charged withN-(3-(N-(3-chloroquinoxalin-2-yl)sulfamoyl)phenyl)-2-(dimethylamino)acetamide(62 mg, 0.147 mmol), the desired aniline (0.567 mmol, 4 eq), and 1.0 mLof toluene. The vessel was sealed and the reaction mixture was heatedunder microwave radiation for 60 min at 180° C. in a CEM Discovermicrowave instrument. The solvent was removed on a rotary-evaporator.Purification of the final product was done by preparatory HPLC withNH₄OAc/ACN as eluent to yield2-(dimethylamino)-N-(3-(N-(3-(4-fluoro-3-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl).

The following compounds were prepared according to the above Examples.

Example 4172-(dimethylamino)-N-(3-(N-(3-(4-fluoro-3-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide

2-(dimethylamino)-N-(3-(N-(3-(4-fluoro-3-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl).¹H-NMR (400 MHz, CDCl₃): δ 9.47 (s, 1H), 8.36 (s, 1H), 8.29 (s, 1H),7.91-7.87 (d, 1H), 7.80-7.73 (m, 2H), 7.66-7.63 (d, 1H), 7.53-7.47 (t,1H), 7.43-7.30 (m, 4H), 7.10-7.04 (t, 1H), 6.55-5.95 (br s, 1H), 3.96(s, 3H), 3.12 (s, 2H), 2.39 (s, 6H), 2.08 (s, 3H(Ac0H); MS (EI)C₂₅H₂₅FN₆O₄S: 525 (MH⁺).

Example 4182-(dimethylamino)-N-(3-(N-(3-(4-fluoro-3-methylphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide

MS (EI) C₂₅H₂₅FN₆O₃S: 509 (MH⁺).

Example 4192-(dimethylamino)-N-(3-(N-(3-(3,5-dimethylphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide

MS (EI) C₂₆H₂₈N₆O₃S: 505 (MH⁺).

Example 420N-(3-(N-(3-(2,4-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(dimethylamino)acetamide

MS (EI) C₂₆H₂₈N₆O₅S: 537 (MH⁺).

Example 421N-(3-(N-(3-(2,3-dihydro-1H-inden-5-ylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-(dimethylamino)acetamide

MS (EI) C₂₇H₂₈N₆O₃S: 517 (MH⁺).

Example 422 Procedure 5N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)-4-isopropoxybenzenesulfonamide

N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)-4-isopropoxybenzenesulfonamide:A solution of 2,3-dichloroquinoxaline (2.0 mL, 0.38 M) was combined withK₂CO₃ (105 mg, 0.76 mmol) in a glass vial. A solution of4-isopropoxybenzene sulfonamide (1.75 mL, 0.43 M) was added and thesolution was stirred overnight at 125° C. After cooling, acetic acid (45mL, 0.79 mmol) and 3,5-dimethoxyaniline (230 mg, 1.5 mmol) were added.The reaction mixture was stirred again at 125° C. overnight. Uponcooling, the reaction mixture was diluted with 8 mL of methanol and then8 mL of water. The precipitate was collected by filtration andrecrystallized from N,N-dimethylacetamide/water to give 45 mg ofproduct. ¹H-NMR (400 MHz, d₆-DMSO): 12.16 (bs, 1H), 8.93 (s, 1H), 8.03(d, 2H), 7.92 (bs, 1H), 7.56 (d, 1H), 7.36 (m, 4H), 7.07 (d, 2H), 6.24(s, 1H), 4.72 (m, 1H), 3.76 (s, 6H), 1.27 (d, 6H); MS (EI) C₂₅H₂₆N₄0₅S:495 (MH⁺).

The remaining examples were synthesized in similar fashion. In the caseswhere the product did not precipitate, the mixture was purified byreverse phase HPLC.

Example 4233-chloro-N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)-4-methylbenzenesulfonamide

¹H-NMR (400 MHz, d₆-DMSO): 12.31 (bs, 1H), 8.96 (s, 1H), 8.18 (s, 1H),7.98 (d, 1H), 7.92 (bs, 1H), 7.58 (d, 2H), 7.43-7.33 (m, 4H), 6.24 (t,1H), 3.76 (s, 6H), 2.39 (s, 3H); MS (EI) C₂₃H₂₁ClN₄0₄S: 485 (MH⁺).

Example 424N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)naphthalene-1-sulfonamide

MS (EI) C₂₆H₂₂N₄O₄S: 487 (MH⁺).

Example 425N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)-4-fluorobenzenesulfonamide

MS (EI) C₂₂H₁₉FN₄O₄S: 455 (MH⁺).

Example 426N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)-3-fluorobenzenesulfonamide

MS (EI) C₂₂H₁₉FN₄O₄S: 455 (MH⁺).

Example 427N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)-3-(trifluoromethyl)benzenesulfonamide

MS (EI) C₂₃H₁₉F₃N₄O₄S: 505 (MH⁺).

Example 428N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)-4-(trifluoromethyl)benzenesulfonamide

MS (EI) C₂₃H₁₉F₃N₄O₄S: 505 (MH⁺).

Example 4292-cyano-N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)benzenesulfonamide

MS (EI) C₂₃H₁₉N₅O₄S: 462 (MH⁺).

Example 430N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)-4-(trifluoromethoxy)benzenesulfonamide

MS (EI) C₂₃H₁₉F₃N₄O₅S: 521 (MH⁺).

Example 431N-(4-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide

MS (EI) C₂₄H₂₃N₅O₅S: 494 (MH⁺).

Example 432N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)-4-fluoro-2-methylbenzenesulfonamide

MS (EI) C₂₃H₂₁FN₄O₄S: 469 (MH⁺).

Example 433N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)-2-methylbenzenesulfonamide

MS (EI) C₂₃H₂₂N₄O₄S: 451 (MH⁺).

Example 4342-chloro-N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)benzenesulfonamide

MS (EI) C₂₂H₁₉ClN₄O₄S: 471 (MH⁺).

Example 435N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)-3,5-difluorobenzenesulfonamide

MS (EI) C₂₂H₁₈F₂N₄O₄S: 473 (MH⁺).

Example 4363,5-dichloro-N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)benzenesulfonamide

MS (EI) C₂₂H₁₈Cl₂N₄O₄S: 505 (MH⁺).

Example 437N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)-3-fluoro-4-methylbenzenesulfonamide

MS (EI) C₂₃H₂₁FN₄O₄S: 469 (MH⁺).

Example 438N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)-2-(trifluoromethyl)benzenesulfonamide

MS (EI) C₂₃H₁₉F₃N₄O₄S: 505 (MH⁺).

Example 4394-cyano-N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)benzenesulfonamide

MS (EI) C₂₃H₁₉N₅O₄S: 462 (MH⁺).

Example 440N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)-1-phenylmethanesulfonamide

MS (EI) C₂₃H₂₂N₄O₄S: 451 (MH⁺).

Example 4414,5-dichloro-N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)thiophene-2-sulfonamide

MS (EI) C₂₀H₁₆Cl₂N₄O₄S₂: 511 (MH⁺).

Example 4421-(3-chlorophenyl)-N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)methanesulfonamide

MS (EI) C₂₃H₂₁ClN₄O₄S: 485 (MH⁺).

Example 443N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)-2,5-dimethylthiophene-3-sulfonamide

MS (EI) C₂₂H₂₂N₄O₄S₂: 471 (MH⁺).

Example 444N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)-3,5-bis(trifluoromethyl)benzenesulfonamide

MS (EI) C₂₄H₁₈F₆N₄O₄S: 573 (MH⁺).

Example 445N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)-4-fluoro-3-(trifluoromethyl)benzenesulfonamide

MS (EI) C₂₃H₁₈F₄N₄O₄S: 523 (MH⁺).

Example 4465-chloro-N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)-1,3-dimethyl-1H-pyrazole-4-sulfonamide

MS (EI) C₂₁H₂₁ClN₆O₄S: 489 (MH⁺).

Example 4475-chloro-N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)-2-methoxybenzenesulfonamide

MS (EI) C₂₃H₂₁ClN₄O₅S: 501 (MH⁺).

Example 4485-bromo-N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)-2-methoxybenzenesulfonamide

MS (EI) C₂₃H₂₁BrN₄O₅S: 545 (MH⁺).

Example 4492,5-dichloro-N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)thiophene-3-sulfonamide

MS (EI) C₂₀H₁₆Cl₂N₄O₄S₂: 511 (MH⁺).

Example 450N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)-3,5-dimethylisoxazole-4-sulfonamide

MS (EI) C₂₁H₂₁N₅O₅S: 456 (MH⁺).

Example 451N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)-2,5-dimethoxybenzenesulfonamide

MS (EI) C₂₄H₂₄N₄O₆S: 497 (MH⁺).

Example 4523-chloro-N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)-4-fluorobenzenesulfonamide

MS (EI) C₂₂H₁₈ClFN₄O₄S: 489 (MH⁺).

Example 453N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)biphenyl-4-sulfonamide

MS (EI) C₂₈H₂₄N₄O₄S: 513 (MH⁺).

Example 4544-(difluoromethoxy)-N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)benzenesulfonamide

MS (EI) C₂₃H₂₀F₂N₄O₅S: 503 (MH⁺).

Example 455N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)-3-(methylsulfonyl)benzenesulfonamide

MS (EI) C₂₃H₂₂N₄O₆S₂: 515 (MH⁺).

General Procedure 6

N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)azetidine-3-carboxamide(125 mg, 0.23 mmol) was dissolved into 5 mL DCE in a 10 mL round-bottomflask. DIPEA (1.17 mmol, 5.0 eq.) was then added with stirring followedby acid chloride (0.47 mmol, 2.0 eq.). The reaction was then stirred atroom temperature for 1 hour or until complete as indicated by LCMS. Thesolvent was subsequently removed under reduced pressure on a rotaryevaporator. The crude material was then redissolved in methanol.Purification of the final product was accomplished by preparatoryreverse-phase HPLC with the eluents 25 mM aqueous NH₄OAc/CAN. A WatersFractionlynx preparative reverse-phase HPLC; equipped with a WatersSunFire Prep C18, OCD 5 □M, 30×70 mm column and running a 5-100%gradient with a binary solvent system of 25 mM ammonium acetate inwater/acetonitrile; was used to carry out the purification.

The following title compounds were prepared according to GeneralProcedure 6.

Example 456N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-1-propionylazetidine-3-carboxamide

¹H-NMR (400 MHz, d₆-DMSO): 12.40 (s, 1H), 10.45 (s, 1H), 8.88 (s, 1H),8.40 (s, 1H), 7.93 (s, 1H), 7.82 (d, 1H), 7.77 (d, 1H), 7.60-7.45 (m,2H), 7.41-7.30 (m, 4H), 6.24 (s, 1H), 4.26 (t, 1H), 4.22-4.17 (m, 1H),3.99 (t, 1H), 3.95-3.89 (m, 1H), 3.76 (s, 6H), 3.59-3.45 (m, 1H), 2.05(dd, 2H), 0.95 (t, 3H); MS (EI) C₂₉H₃₀N₆0₆S: 591 (MH⁺).

Example 4571-acetyl-N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)azetidine-3-carboxamide

MS (EI) C₂₈H₂₈N₆O₆S: 577 (MH⁺).

Example 4581-(cyclopropanecarbonyl)-N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)azetidine-3-carboxamide

MS (EI) C₃₀H₃₀N₆O₆S: 603 (MH⁺).

General Procedure 7

To a solution ofN-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)azetidine-3-carboxamide(110 mg, 0.19 mmol) in 3 mL of DCE and 200 μL of DMF, aldehyde (0.77mmol, 4.0 eq.) was added slowly followed by tetramethylammoniumtriacetoxyborohydride (1.16 mmol, 6.0 eq). The reaction was stirred atroom temperature overnight. LC/MS indicated the reaction was completed.The solvent was subsequently removed under reduced pressure on a rotaryevaporator. The crude material was then redissolved in methanol.Purification of the final product was accomplished by preparatoryreverse-phase HPLC with the eluents 25 mM aqueous NH₄OAc/CAN. A WatersFractionlynx preparative reverse-phase HPLC; equipped with a WatersSunFire Prep C18, OCD 5 □M, 30×70 mm column and running a 5-100%gradient with a binary solvent system of 25 mM ammonium acetate inwater/acetonitrile; was used to carry out the purification.

The following title compounds were prepared according to GeneralProcedure 7.

Example 459N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-1-ethylazetidine-3-carboxamide

¹H-NMR (400 MHz, d₆-DMSO): 10.29 (s, 1H), 8.82 (s, 1H), 8.25 (t, 1H),7.75-7.68 (m, 2H), 7.43-7.38 (m, 1H), 7.375-7.340 (m, 1H), 7.338-7.310(d, 2H), 7.305-7.262 (m, 1H), 7.15-7.08 (m, 2H), 6.56 (s, 1H), 6.15 (t,1H), 4.15-4.08 (m, 2H), 4.06-3.95 (m, 2H), 3.78 (s, 6H), 3.65-3.56 (m,1H), 3.12-3.04 (m, 2H), 1.03 (t, 3H); MS (EI) C₂₈H₃₀N₆0₅S: 563 (MH⁺).

Example 4601-(cyclopropylmethyl)-N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)azetidine-3-carboxamide

MS (EI) C₃₀H₃₂N₆O₅S: 589 (MH⁺).

Example 4611-benzyl-N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)azetidine-3-carboxamide

MS (EI) C₃₃H₃₂N₆O₅S: 625 (MH⁺).

Example 462N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-1-(furan-2-ylmethyl)azetidine-3-carboxamide

MS (EI) C₃₁H₃₀N₆O₆S: 615 (MH⁺).

Example 4631-((1H-imidazol-5-yl)methyl)-N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoylphenyl)azetidine-3-carboxamide

MS (EI) C₃₀H₃₀N₈O₅S: 615 (MH⁺).

General Library Procedure 8

Into a small 1 dram vial was added3-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)benzoicacid (61 mg, 0.13 mmol, 1.1 equiv). The acid was dissolved in 1 mL ofDMA and DIPEA (42 uL, 0.24 mMol, 2 equiv) was added then added to thesolution. The amine reagent (1 mL of 0.12 M solution in DMA) was addedto solution with stirring followed by HATU (64 mg, 0.17 mMol, 1.4equiv). Reaction was stirred overnight at room temperature. Uponcompletion as indicated by LCMS analysis, 2 mL of methanol was added tothe solution. Preparative reverse-phase HPLC was used to isolate thedesired product directly from this crude reaction solution. A WatersFractionlynx preparative reverse-phase HPLC; equipped with a WatersSunFire Prep C18, OCD 5 μM, 30×70 mm column and running a 5-100%gradient with a binary solvent system of 25 mM ammonium acetate inwater/acetonitrile; was used to carry out the purification.

The following compounds were prepared according to General LibraryProcedure 8.

Example 4643-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)-N-(3-(dimethylamino)propyl)benzamide

3-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)-N-(3-(dimethylamino)propyl)benzamide:¹H NMR (400 MHz, d₆-DMSO): 9.44 (s, 1H), 8.94 (s, 1H), 8.79 (t, 1H),8.54 (s, 1H), 8.24 (d, 1H), 7.87 (d, 1H), 7.48 (m, 3H), 7.33 (d, 1H),7.18 (m, 2H), 6.60 (dd, 1H), 3.82 (1H), 3.04 (m, 3H), 2.51 (m, 5H), 1.91(s, 1H), 1.86 (m, 3H); MS (EI) for C₂₇H₂₉ClN₆O₄S: 569 (MH⁺).

Example 4653-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)-N-(1-methylazetidin-3-yl)benzamide

3-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)-N-(1-methylazetidin-3-yl)benzamide:¹H NMR (400 MHz, d₆-DMSO): 9.43 (s, 1H), 9.23 (d, 1H), 8.94 (d, 1H),8.58 (s, 1H), 8.29 (d, 1H), 7.89 (d, 1H), 7.56 (t, 1H), 7.47 (d, 1H),7.44 (d, 1H), 7.33 (d, 1H), 7.18 (m, 2H), 6.60 (dd, 1H), 4.81 (m, 1H),4.33 (m, 2H), 4.19 (m, 2H), 3.82 (s, 1H), 2.51 (s, 3H); MS (EI) forC₂₆H₂₅ClN₆O₄S: 553 (MH⁺).

Example 4663-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)-N-(pyridin-4-ylmethyl)benzamide

MS (EI) C₂₈H₂₃ClN₆O₄S: 575 (MH⁺).

Example 4673-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)-N-(3-(dimethylamino)propyl)benzamide

MS (EI) C₂₈H₂₆ClN₇O₄S: 592 (MH⁺).

Example 468N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)-3-(2,2-dimethylhydrazinecarbonyl)benzenesulfonamide

MS (EI) C₂₄H₂₃ClN₆O₄S: 527 (MH⁺).

Example 4693-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)-N-(2-methoxyethyl)benzamide

MS (EI) C₂₅H₂₄ClN₅O₅S: 542 (MH⁺).

Example 470N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)-3-(4-methylpiperazine-1-carbonyl)benzenesulfonamide

MS (EI) C₂₇H₂₇ClN₆O₄S: 567 (MH⁺).

Example 4713-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)-N-(2-(pyrrolidin-1-yl)ethyl)benzamide

MS (EI) C₂₈H₂₉ClN₆O₄S: 581 (MH⁺).

Example 4723-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)-N-(2-(pyridin-4-yl)ethyl)benzamide

MS (EI) C₂₉H₂₅ClN₆O₄S: 589 (MH⁺).

Example 473N-(2-(1H-imidazol-4-yl)ethyl)-3-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)benzamide

MS (EI) C₂₇H₂₄ClN₇O₄S: 578 (MH⁺).

Example 4743-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)-N-(piperidin-1-yl)benzamide

MS (EI) C₂₇H₂₇ClN₆O₄S: 567 (MH⁺).

Example 4753-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)-N-(2-hydroxyethyl)benzamide

MS (EI) C₂₄H₂₂ClN₅O₅S: 528 (MH⁺).

Example 4763-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)-N-(3-ethoxypropyl)benzamide

MS (EI) C₂₇H₂₈ClN₅O₅S: 570 (MH⁺).

Example 4773-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)-N-(3-(pyrrolidin-1-yl)propyl)benzamide

MS (EI) C₂₉H₃₁ClN₆O₄S: 595 (MH⁺).

Example 4781113-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)-N-(3-(diethylamino)propyl)benzamide

MS (EI) C₂₉H₃₃ClN₆O₄S: 597 (MH⁺).

Example 4793-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)-N-(3-(2-oxopyrrolidin-1-yl)propyl)benzamide

MS (EI) C₂₉H₂₉ClN₆O₅S: 609 (MH⁺).

Example 4803-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)-N-(pyridin-2-ylmethyl)benzamide

MS (EI) C₂₈H₂₃ClN₆O₄S: 575 (MH⁺).

Example 4813-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)-N-(2-cyanoethyl)-N-methylbenzamide

MS (EI) C₂₆H₂₃ClN₆O₄S: 551 (MH⁺).

Example 4823-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)-N-(2-cyanoethyl)-N-ethylbenzamide

MS (EI) C₂₇H₂₅ClN₆O₄S: 565 (MH⁺).

Example 4833-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)-N-(2-(ethylthio)ethyl)benzamide

MS (EI) C₂₆H₂₆ClN₅O₄S₂: 572 (MH⁺).

Example 4843-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)-N-(3-propoxypropyl)benzamide

MS (EI) C₂₈H₃₀ClN₅O₅S: 584 (MH⁺).

Example 4853-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)-N-(5-(diethylamino)pentan-2-yl)benzamide

MS (EI) C₃₁H₃₇ClN₆O₄S: 625 (MH⁺).

Example 4863-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)-N-(3-methoxypropyl)benzamide

MS (EI) C₂₆H₂₆ClN₅O₅S: 556 (MH⁺).

Example 4873-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)-N-(3-morpholinopropyl)benzamide

MS (EI) C₂₉H₃₁ClN₆O₅S: 611 (MH⁺).

Example 4883-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)-N-(pyridin-3-ylmethyl)benzamide

MS (EI) C₂₈H₂₃ClN₆O₄S: 575 (MH⁺).

Example 4893-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)-N-(2-cyanoethyl)benzamide

MS (EI) C₂₅H₂₁ClN₆O₄S: 537 (MH⁺).

Example 4903-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)-N-(1-methoxypropan-2-yl)benzamide

MS (EI) C₂₆H₂₆ClN₅O₅S: 556 (MH⁺).

Example 4913-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)-N-(2-(methylthio)ethyl)benzamide

MS (EI) C₂₅H₂₄ClN₅O₄S₂: 558 (MH⁺).

Example 4923-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)-N-(3-(dimethylamino)propyl)-N-methylbenzamide

MS (EI) C₂₈H₃₁ClN₆O₄S: 583 (MH⁺).

Example 4933-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)-N-(3-isopropoxypropyl)benzamide

MS (EI) C₂₈H₃₀ClN₅O₅S: 584 (MH⁺).

Example 4943-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)-N-(2-(dimethylamino)ethyl)-N-ethylbenzamide

MS (EI) C₂₈H₃₁ClN₆O₄S: 583 (MH⁺).

Example 495N-(3-butoxypropyl)-3-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)benzamide

MS (EI) C₂₉H₃₂ClN₅O₅S: 598 (MH⁺).

Example 4963-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)-N-(2-(diethylamino)ethyl)benzamide

MS (EI) C₂₈H₃₁ClN₆O₄S: 583 (MH⁺).

Example 497XEL-04286749 methyl3-(3-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)benzamido)propanoate

MS (EI) C₂₆H₂₄ClN₅O₆S: 570 (MH⁺).

Example 4983-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)-N-methyl-N-propylbenzamide

MS (EI) C₂₆H₂₆ClN₅O₄S: 540 (MH⁺).

Example 499 ethyl3-(3-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)benzamido)propanoate

MS (EI) C₂₇H₂₆ClN₅O₆S: 584 (MH⁺).

Example 5003-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)-N-(2-(piperidin-1-yl)ethyl)benzamide

MS (EI) C₂₉H₃₁ClN₆O₄S: 595 (MH⁺).

Example 5013-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)-N-((1-ethylpyrrolidin-2-yl)methyl)benzamide

MS (EI) C₂₉H₃₁ClN₆O₄S: 595 (MH⁺).

Example 502N-(2-(bis(2-hydroxyethyl)amino)ethyl)-3-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)benzamide

MS (EI) C₂₈H₃₁ClN₆O₆S: 615 (MH⁺).

Example 503N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)-3-(3-(diethylamino)pyrrolidine-1-carbonyl)benzenesulfonamide

MS (EI) C₃₀H₃₃ClN₆O₄S: 609 (MH⁺).

Example 5043-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)-N-methyl-N-(1-methylpyrrolidin-3-yl)benzamide

MS (EI) C₂₈H₂₉ClN₆O₄S: 581 (MH⁺).

Example 505N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)-3-(3-(dimethylamino)pyrrolidine-1-carbonyl)benzenesulfonamide

MS (EI) C₂₈H₂₉ClN₆O₄S: 581 (MH⁺).

Example 5063-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)-N-(2-methyl-1-morpholinopropan-2-yl)benzamide

MS (EI) C₃₀H₃₃ClN₆O₅S: 625 (MH⁺).

Example 5073-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)-N-(1H-pyrrol-1-yl)benzamide

MS (EI) C₂₆H₂₁ClN₆O₄S: 549 (MH⁺).

Example 5083-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)-N-(3-oxopyrazolidin-4-yl)benzamide

MS (EI) C₂₅H₂₂ClN₇O₅S: 568 (MH⁺).

Example 509N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)-3-(2-((dimethylamino)methyl)piperidine-1-carbonyl)benzenesulfonamide

MS (EI) C₃₀H₃₃ClN₆O₄S: 609 (MH⁺).

Example 510N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)-3-(2-(piperidin-1-ylmethyl)piperidine-1-carbonyl)benzenesulfonamide

MS (EI) C₃₃H₃₇ClN₆O₄S: 649 (MH⁺).

Example 5113-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)-N-(1-ethylpiperidin-3-yl)benzamide

MS (EI) C₂₉H₃₁ClN₆O₄S: 595 (MH⁺).

General Procedure 8A

The General Library Procedure outlined in Procedure 8 was used toincorporate a number of amines that contained a second amine groupprotected as the tert-butylcarbamate. A subsequent deprotection afterHPLC purification was performed to unmask this second amine group. Intoa small 1 dram vial was added3-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)benzoicacid (61 mg, 0.13 mmol, 1.1 equiv). The acid was dissolved in 1 mL ofDMA and DIPEA (42 uL, 0.24 mmol, 2 equiv) was added then added to thesolution. The mono-Boc-protected diamine reagent (1 mL of 0.12 Msolution in DMA, 1 equiv) was added to solution with stirring followedby HATU (64 mg, 0.17 mmol, 1.4 equiv). Reaction was stirred overnight atroom temperature. Upon completion as indicated by LCMS analysis, 2 mL ofmethanol was added to the solution. Preparative reverse-phase HPLC wasused to isolate the desired product directly from this crude reactionsolution. A Waters Fractionlynx preparative reverse-phase HPLC; equippedwith a Waters SunFire Prep C18, OCD 5 μM, 30×70 mm column and running a5-100% gradient with a binary solvent system of 25 mM ammonium acetatein water/acetonitrile; was used to carry out the purification. Theproduct fractions were combined and concentrated to dryness underreduced pressure by rotary evaporation. A solution of 4 N HCl in dioxane(2 mL) was added. The solution was then stirred at room temperatureuntil no starting material was detected. The deprotected productprecipitated out of solution as an HCL salt and was collected byfiltration, washed with ether and dried under vacuum.

The following compounds were prepared according to General Procedure 8A

Example 5123-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)-N-(piperidin-3-yl)benzamide

3-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)-N-(piperidin-3-yl)benzamide:¹H NMR (400 MHz, d₆-DMSO): 12.82 (s, 1H), 9.12 (s, 1H), 9.04 (s, 1H),8.85 (d, 1H), 8.65 (s, 1H), 8.55 (s, 1H), 8.18 (m, 1H), 7.98 (s, 1H),7.69 (m, 2H), 7.43 (m, 2H), 6.69 (dd, 1H), 4.21 (s, 1H), 3.83 (s, 3H),3.69 (m, 1H), 3.48 (m, 1H), 3.18 (s, 1H), 2.84 (q, 2H), 1.91 (s, 2H); MS(EI) for C₂₇H₂₇ClN₆O₄S: 567 (MH⁺).

Example 5133-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)-N-(piperidin-2-ylmethyl)benzamide

3-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)-N-(piperidin-2-ylmethyl)benzamide:NMR (400 MHz, d₆-DMSO): 12.78 (s, 1H), 9.16 (s, 1H), 9.09 (s, 1H), 8.79(s, 1H), 8.59 (d, 2H), 8.22 (t, 2H), 7.99 (s, 1H), 7.74 (t, 1H), 7.66(s, 1H), 7.42 (m, 2H), 6.69 (dd, 1H), 3.82 (s, 3H), 3.69 (dd, 1H), 3.57(m, 1H), 3.50 (m, 3H), 3.22 (s, 2H), 2.82 (d, 1H), 1.68 (m, 5H); MS (EI)for C₂₈H₂₉ClN₆O₄S: 581 (MH⁺).

Example 5143-(3-aminopyrrolidine-1-carbonyl)-N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)benzenesulfonamide

MS (EI) C₂₆H₂₅ClN₆O₄S: 553 (MH⁺).

Example 5153-(3-aminoazetidine-1-carbonyl)-N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)benzenesulfonamide

MS (EI) C₂₅H₂₃ClN₆O₄S: 539 (MH⁺).

Example 5163-(3-aminopiperidine-1-carbonyl)-N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)benzenesulfonamide

MS (EI) C₂₇H₂₇ClN₆O₄S: 567 (MH⁺).

Example 5173-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)-N-(pyrrolidin-3-yl)benzamide

MS (EI) C₂₆H₂₅ClN₆O₄S: 553 (MH⁺).

Example 518N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)-3-(3-(methylamino)pyrrolidine-1-carbonyl)benzenesulfonamide

MS (EI) C₂₇H₂₇ClN₆O₄S: 567 (MH⁺).

Example 519N-(2-aminoethyl)-3-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)benzamide

MS (EI) C₂₄H₂₃ClN₆O₄S: 527 (MH⁺).

Example 5203-(4-amino-3-oxopyrazolidine-1-carbonyl)-N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)benzenesulfonamide

MS (EI) C₂₅H₂₂ClN₇O₅S: 568 (MH⁺).

Example 5213-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)-N-((1-methylpiperidin-2-yl)methyl)benzamide

A measured amount of3-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)-N-(piperidin-2-ylmethyl)benzamide(299 mg, 0.51 mmol, 1 eq) was dissolved in 2.3 mL of DMA. Formic acid(388 ul, 10.28 mmol, 20 eq) was added to solution with stirring followedby the addition of formaldehyde (508 ul of 37% aq. solution). Thereaction was then stirred at room temperature overnight. Analysis of analiquot of the reaction mixture by LCMS indicated the completeconsumption of starting material. The reaction was diluted with methanol(2 mL). Preparative reverse-phase HPLC was used to isolate the desiredproduct directly from the crude reaction mixture. A Waters Fractionlynxpreparative reverse-phase HPLC; equipped with a Waters SunFire Prep C18,OCD 5 □M, 30×70 mm column and running a 5-100% gradient with a binarysolvent system of 25 mM ammonium acetate in water/acetonitrile; was usedto carry out the purification. ¹H NMR (400 MHz, d₆-DMSO): 9.44 (s, 1H),8.94 (s, 1H), 8.79 (t, 1H), 8.57 (s, 1H), 8.27 (d, 1H), 7.90 (d, 1H)7.54 (t, 1H), 7.46 (d, 1H), 7.39 (d, 1H), 7.33 (d, 1H), 7.18 (m, 2H),6.60 (dd, 1H), 3.82 (s, 3H), 3.59 (m, 2H), 3.00 (s, 1H), 2.90 (s, 3H),1.62 (m, 7H); MS (EI) for C₂₉H₃₁ClN₆O₄S: 595 (MH⁺).

Example 5223-(N-(3-(2-chloro-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)-N-(1-methylpiperidin-3-yl)benzamide

The title compound was prepared according to the above Examples. ¹H NMR(400 MHz, d₆-DMSO): 9.43 (s, 1H), 8.93 (s, 1H), 8.59 (s, 1H), 8.24 (d,1H), 7.87 (d, 1H), 7.47 (m, 2H), 7.40 (d, 1H), 7.33 (d, 1H), 7.19 (m,2H), 6.60 (dd, 1H), 4.21 (s, 1H), 3.82 (s, 1H), 2.76 (s, 1H), 2.50 (m,7H), 1.91 (m, 2H), 1.63 (m, 2H); MS (EI) for C₂₈H₂₉ClN₆O₄S: 581 (MH⁺).

Biological Assays

The compounds of the invention demonstrated the ability to bind to PI3Kwhen tested in the assays described in Section II above. In anotherembodiment, the compounds in Section II and Section III bind to the PI3Kwith a binding affinity, for example, of about 50 μM or less, 20 μM orless, 10 μM or less, 5 μM or less, 2.5 μM or less or 1 μM or less. In anadvantageous embodiment, the IC50 of the binding compounds is about 0.5μM or less, about 0.3 μM or less, about 0.1 μM or less, about 0.08 μM orless, about 0.06 μM or less, about 0.05 μM or less, about 0.04 μM orless, 0.03 μM or less, in another embodiment, about 0.03 μM or less.

Biological Models

Several biological models were used to test the efficacy of a MEKcompound of Formula I, Ia, Ic, Id, II, III, IV, or V in combination witha PI3K compound of Formula VI, VIa, VIb or VII or a PI3K compound ofFormula VIII, VIIIa, VIIIb, or IX in inhibiting tumor cellproliferation. In brief, either A2058 or WM-266 melanoma cell lines(ATCC) were transplanted intradermally in the hindflank of athymic nudemice (Jackson Laboratories). Both cell lines contain the B-RAF V600Emutation (Solit et al., Nature 439: pages 358-362, February 2006) andthe PTEN gene is deleted. The xenograft was allowed to grow and dividefor 10 days. Starting on day 10, mice were treated daily with a vehiclecontrol or with a selected compound from section I (MEK inhibitor ofFormula I, Ia, Ic, Id, II, III, IV, or V) either alone or in combinationwith a compound from section II (PI3K inhibitor of Formulae Formula VI,VIa, VIb or VII) or a compound from section III (PI3K inhibitor ofFormulae Formula VIII, VIIIa, VIIIb, or IX). The xenografts were allowedto grow for another 15 days and then the tumors were weighed.

Mice treated with the MEK inhibitor alone exhibited a 50-75% reductionin tumor growth over the 15 day treatment period. Mice carrying theA2058 xenograft and treated with a select MEK inhibitor at 10 mgs/kgshowed a 60% reduction in tumor growth relative to mice treated withvehicle alone. Mice carrying the A2058 xenograft and treated withvehicle had a mean tumor weight of approximately 1100 mgs versus micewho were treated with the select MEK inhibitor who had a mean tumorweight of 450 mgs. Mice carrying the WM-266 xenograft and treated withvehicle had a mean tumor weight of 700 mgs while mice carrying the samexenograft and treated with the select MEK inhibitor had a mean tumorweight of 200 mgs. The MEK inhibitor inhibited the tumor growth of bothtumors by 60-75% over the 15 day period of treatment.

Mice treated with a combination of MEK inhibitor and a selected SectionII or Section III PI3K inhibitor also exhibited a reduction in tumorgrowth over the 15 day treatment period. Mice carrying the A2058xenograft and treated with a select Section III PI3K inhibitor at 100mgs/kg exhibited a 65% reduction in growth relative to animals treatedwith the vehicle alone (mean tumor size of 375 mgs for Section III PI3Kinhibitor treated animals vs 1100 mgs for vehicle treated animals).Animals treated with a combination of a select MEK inhibitor (10 mgs/kg)and a selected Section III PI3K inhibitor (100 mgs/kg) exhibited an 80%reduction in tumor growth over the 15 day treatment period (mean tumorsize of 200 mgs for the tumors treated with the combination of compoundsvs 1100 mgs for the vehicle treated tumors).

Mice carrying the A2058 xenograft and treated with a select Section IIPI3K inhibitor at 100 mgs/kg exhibited a 65% reduction in growthrelative to animals treated with the vehicle alone (mean tumor size of350 mgs for PI3K inhibitor treated animals vs 1100 mgs for vehicletreated animals). Animals treated with a combination of a select MEKinhibitor (10 mgs/kg) and a selected Section II PI3K inhibitor (100mgs/kg) exhibited an 75% reduction in tumor growth over the 15 daytreatment period (mean tumor size of 250 mgs for the tumors treated withthe combination of compounds vs 1100 mgs for the vehicle treatedtumors).

Similar results were observed in animals carrying the WM-266 xenograftand treated with the same combination of drugs. Mean tumor weights forthe animals treated with the vehicle alone were 700 mgs after 15 days oftreatment. Animals that had received the Section III PI3K or Section IIPI3K inhibitors exhibited a 50% reduction in tumor growth (mean tumorsize of 500 mgs for the tumors treated with each compound) and an 85%reduction in tumor growth for tumors treated with the combination of aselect MEK and either the Section II PI3K or Section III PI3K inhibitors(mean tumor size of 100 mgs after 15 days of combination treatment).

Xenographs treated with the combination of a select MEK inhibitor andeither a select Section III PI3K inhibitor or a select Section II PI3Kinhibitor exhibited a greater reduction in tumor growth than tumorstreated with either compound alone.

The foregoing invention has been described in some detail by way ofillustration and example, for purposes of clarity and understanding. Theinvention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications may be made while remainingwithin the spirit and scope of the invention. It will be obvious to oneof skill in the art that changes and modifications may be practicedwithin the scope of the appended claims. Therefore, it is to beunderstood that the above description is intended to be illustrative andnot restrictive. The scope of the invention should, therefore, bedetermined not with reference to the above description, but shouldinstead be determined with reference to the following appended claims,along with the full scope of equivalents to which such claims areentitled. All patents, patent applications and publications cited inthis application are hereby incorporated by reference in their entiretyfor all purposes to the same extent as if each individual patent, patentapplication or publication were so individually denoted.

1. A method of treating cancer which method comprises administering to apatient a therapeutically effective amount of a compound of Formula Ia,Ic, Id, II, or V or a pharmaceutically acceptable composition, thereof,in combination with a compound(s) selected from the group consisting ofa compound of Formula VIa, VIb, VII, VIIIa, and VIIIb, or apharmaceutically acceptable composition thereof, where Formula Ia is asfollows:

and optionally as a pharmaceutically acceptable salt or solvate thereof,wherein the A ring represents an arylene or heteroarylene group and theA ring is optionally substituted with one, two, three or four groupsselected from R¹⁰, R¹², R¹⁴, and R¹⁶ where R¹⁰, R¹², R¹⁴, and R¹⁶ areindependently hydrogen, lower alkanyl, lower alkenyl, lower alkynyl,halo, haloalkoxy, hydroxy, lower alkoxy, amino, alkylamino,dialkylamino, haloalkyl, —NHS(O)₂R⁸, —CN, —C(O)R⁸, —C(O)OR⁸,—C(O)NR⁸R^(8′) or —NR⁸C(O)R^(8′); X is lower alkyl, halo, haloalkyl, orhaloalkoxy; R¹, R², R³, R⁴, R⁵ and R⁶ are independently hydrogen, halo,nitro, —NR⁸R^(8′), —OR⁸, —NHS(O)₂R⁸, —CN, —S(O)_(m)R⁸, —S(O)₂NR⁸R^(8′),—C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′), —NR⁸C(O)OR^(8′),—NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′), —NR⁸C(O)R^(8′), lower alkanyl,lower alkenyl, lower alkynyl, cycloalkyl, heteroaryl, orheterocycloalkyl; where the lower alkanyl, lower alkenyl, lower alkynyl,cycloalkyl, heteroaryl, and heterocycloalkyl are optionally substitutedwith one, two, three, four, five, six or seven groups independentlyselected from halo, lower alkanyl, haloalkyl, nitro, optionallysubstituted cycloalkyl, optionally substituted heterocycloalkyl,optionally substituted aryl, optionally substituted arylalkyl,optionally substituted heteroaryl, —OR⁸, —NR⁸R^(8′), —NHS(O)₂R⁹, —CN,—S(O)_(m)R⁹, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′), —NR⁸C(O)NR^(8′)R^(8″),—NR⁸C(O)OR^(8′), and —NR⁸C(O)R^(8′); or one of R¹ and R² together withthe carbon to which they are attached, R³ and R⁴ together with thecarbon to which they are attached, and R⁵ and R⁶ together with thecarbon to which they are attached form C(O) or C(═NOH); m is 1 or 2; R⁷is hydrogen, halo or lower alkyl; R⁸, R^(8′) and R^(8″) areindependently hydrogen, hydroxy, alkoxy, substituted alkoxy, loweralkanyl, haloalkyl, lower alkenyl, lower alkynyl, aryl, cycloalkyl,heteroaryl, or heterocycloalkyl; where the lower alkanyl, lower alkenyl,lower alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl areindependently optionally substituted with one, two three, four, or fivegroups independently selected from lower alkanyl, halo, hydroxy,hydroxyalkyl, lower alkoxy, substituted alkoxy, alkoxyalkyl, haloalkyl,carboxy, carboxy ester, nitro, cyano, —S(O)_(n)R³¹ (where n is 0, 1, or2 and R³¹ is alkyl, substituted alkyl, optionally substituted aryl,optionally substituted heterocycloalkyl, or optionally substitutedheteroaryl), —NR³⁴SO₂R^(34a) (where R³⁴ is hydrogen or lower alkyl andR^(34a) is lower alkyl, lower alkenyl, optionally substituted aryl,optionally substituted heterocycloalkyl, optionally substitutedcycloalkyl, or optionally substituted heteroaryl), —SO₂NR³⁵R^(35a)(where R³⁵ is hydrogen or alkyl and R^(35a) is lower alkyl, loweralkenyl, optionally substituted aryl, optionally substitutedheterocycloalkyl, optionally substituted cycloalkyl, or optionallysubstituted heteroaryl), optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, optionallysubstituted arylalkyl, aryloxy, arylalkyloxy, optionally substitutedheteroaryl, —NHC(O)R³² (where R³² is lower alkanyl, lower alkenyl,alkoxy, or cycloalkyl) and —NR³⁰R^(30′) (where R³⁰ and R^(30′) areindependently hydrogen, lower alkyl, or hydroxyalkyl), and —C(O)NHR³³(where R³³ is lower alkanyl, lower alkenyl, lower alkynyl, orcycloalkyl); and R⁹ is lower alkanyl, lower alkenyl, lower alkynyl,aryl, cycloalkyl, heteroaryl, or heterocycloalkyl; where the loweralkanyl, lower alkenyl, lower alkynyl, aryl, cycloalkyl, heteroaryl, andheterocycloalkyl are independently optionally susbstituted with one,two, three, four, or five groups selected from lower alkanyl, halo,hydroxy, haloalkoxy, haloalkyl, amino, alkylamino, and dialkylamino;where Formula Ic is as follows:

and optionally as a pharmaceutically acceptable salt or solvate thereof,wherein R¹⁰, R¹², R¹⁴, and R¹⁶ are independently hydrogen, loweralkanyl, halo, haloalkoxy, hydroxy, lower alkoxy, or haloalkyl; X ishalo; R³ is hydrogen, halo, nitro, —NR⁸R^(8′), —OR⁸, —NHS(O)₂R⁸, —CN,—S(O)_(m)R⁸, —S(O)₂NR⁸R^(8′), —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′),—NR⁸C(O)OR^(8′), —NR⁸C(O)NR^(8′)R^(8″), —NR⁸C(O)OR^(8′), —NR⁸C(O)R^(8′),lower alkanyl, lower alkenyl, lower alkynyl, cycloalkyl, heteroaryl, orheterocycloalkyl; where the lower alkanyl, lower alkenyl, lower alkynyl,cycloalkyl, heteroaryl, and heterocycloalkyl are optionally substitutedwith one, two, three, four, five, six or seven groups independentlyselected from halo, lower alkanyl, haloalkyl, nitro, optionallysubstituted cycloalkyl, optionally substituted heterocycloalkyl,optionally substituted aryl, optionally substituted arylalkyl,optionally substituted heteroaryl, —OR⁸, —NR⁸R^(8′), —NHS(O)₂R⁹, —CN,—S(O)_(m)R⁹, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁸R^(8′), —NR⁸C(O)NR^(8′)R^(8″),—NR⁸C(O)OR^(8′), and —NR⁸C(O)R^(8′); R⁷ is hydrogen, halo or loweralkyl; R⁸, R^(8′) and R^(8″) are independently hydrogen, hydroxy,alkoxy, substituted alkoxy, lower alkanyl, haloalkyl, lower alkenyl,lower alkynyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl; wherethe lower alkanyl, lower alkenyl, lower alkynyl, aryl, cycloalkyl,heteroaryl, and heterocycloalkyl are independently optionallysubstituted with one, two three, four, or five groups independentlyselected from lower alkanyl, halo, hydroxy, hydroxyalkyl, lower alkoxy,substituted alkoxy, alkoxyalkyl, haloalkyl, carboxy, carboxy ester,nitro, cyano, —S(O)_(n)R³¹ (where n is 0, 1, or 2 and R³¹ is alkyl,substituted alkyl, optionally substituted aryl, optionally substitutedheterocycloalkyl, or optionally substituted heteroaryl), —NR³⁴SO₂R^(34a)(where R³⁴ is hydrogen or lower alkyl and R^(34a) is lower alkyl, loweralkenyl, optionally substituted aryl, optionally substitutedheterocycloalkyl, optionally substituted cycloalkyl, or optionallysubstituted heteroaryl), —SO₂NR³⁵R^(35a) (where R³⁵ is hydrogen or alkyland R^(35a) is lower alkyl, lower alkenyl, optionally substituted aryl,optionally substituted heterocycloalkyl, optionally substitutedcycloalkyl, or optionally substituted heteroaryl), optionallysubstituted cycloalkyl, optionally substituted heterocycloalkyl,optionally substituted aryl, optionally substituted arylalkyl, aryloxy,arylalkyloxy, optionally substituted heteroaryl, —NHC(O)R³² (where R³²is lower alkanyl, lower alkenyl, alkoxy, or cycloalkyl) and —NR³⁰R^(30′)(where R³⁰ and R^(30′) are independently hydrogen, lower alkyl, orhydroxyalkyl), and —C(O)NHR³³ (where R³³ is lower alkanyl, loweralkenyl, lower alkynyl, or cycloalkyl); and R⁹ is lower alkanyl, loweralkenyl, lower alkynyl, aryl, cycloalkyl, heteroaryl, orheterocycloalkyl; where the lower alkanyl, lower alkenyl, lower alkynyl,aryl, cycloalkyl, heteroaryl, and heterocycloalkyl are independentlyoptionally susbstituted with one, two, three, four, or five groupsselected from lower alkanyl, halo, hydroxy, haloalkoxy, haloalkyl,amino, alkylamino, and dialkylamino; where Formula Id is as follows:

and optionally as a pharmaceutically acceptable salt or solvate thereof,wherein X, R⁷, R¹⁰, R¹², R¹⁴, R¹⁶, R³, R⁸, and R^(8′) are as definedabove for Formula Ic; where Formula II is as follows:

and optionally as a pharmaceutically acceptable salt or solvate thereof,wherein X, R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ are as defined above forFormula Ia; where Formula V is as follows:

and optionally as a pharmaceutically acceptable salt or solvate thereof,wherein the A ring, R³, R⁴, and R⁴ are as defined above for Formula Ia;where Formula VIa is as follows:

and optionally as a pharmaceutically acceptable salt or hydrate thereof,wherein R¹ is hydrogen, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₃-C₇ cycloalkyl, optionally substituted aryl, optionallysubstituted heteroalicyclic, optionally substitutedheteroalicyclicalkyl, optionally substituted heteroaryl or optionallysubstituted heteroarylalkyl; X is —NR³—; R² is hydrogen, optionallysubstituted C₁-C₆ alkyl, C₃-C₇ cycloalkyl, aryl, aryl-C₁₋₆ alkyl,heteroalicyclic, heterocyclylalkyl, heterocyclyl-aryl- or heteroaryl;where the cycloalkyl, aryl, aryl-C₁₋₆ alkyl, heteroalicyclic,heterocyclylalkyl, heterocyclyl-aryl-, and heteroaryl groups in R² areoptionally substituted with 1, 2, 3, or 4 R⁸ groups; R³ is hydrogen; R⁴is optionally substituted C₁-C₆ alkyl; R⁶ is hydrogen, acyl, phenyl,heteroalicyclic, or heteroaryl; where the phenyl, heteroalicyclic, andheteroaryl in R⁶ are optionally substituted with 1, 2, 3, or 4 R⁹groups; R⁸ at each occurrence is independently hydroxy, halo, haloalkyl,C₁-C₆ alkyl, optionally substituted C₁-C₆ alkoxy, C₁-C₆ alkoxyalkyl,C₁-C₆ alkoxyalkylaminoalkyl, C₁-C₆ alkylcarboxyheterocyclyl,—O—C₁-C₆alkylheterocyclyl, aminoalkyl, optionally substituted C₃-C₇cycloalkyl, optionally substituted aryl, optionally substituted arylC₁-C₆ alkyl, optionally substituted heteroalicyclic, optionallysubstituted heteroalicyclicalkyl, optionally substituted heteroaryl oroptionally substituted heteroarylalkyl; and R⁹ at each occurrence isindependently halo, haloalkyl, haloalkoxy, C₁-C₆ alkyl, C₁-C₆ alkoxy,C₁-C₆ alkoxyalkyl, C₁-C₆ carboxyalkyl, alkoxycarbonyl, aminoalkyl,optionally substituted C₃-C₇ cycloalkyl, optionally substituted aryl,optionally substituted aryl C₁-C₆ alkyl, optionally substituted aryloxy,optionally substituted heteroalicyclic, or optionally substitutedheteroaryl; where Formula VIb is as follows:

and optionally a pharmaceutically acceptable salt or solvate thereof,wherein R¹ is hydrogen, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₃-C₇ cycloalkyl, optionally substituted aryl, optionallysubstituted heteroalicyclic, optionally substitutedheteroalicyclicalkyl, optionally substituted heteroaryl or optionallysubstituted heteroarylalkyl; R⁶ is phenyl, acyl, or heteroaryl whereinthe phenyl and heteroaryl are optionally substituted with 1, 2, 3, or 4R⁹ groups; and R⁹ at each occurrence is independently halo, haloalkyl,haloalkoxy, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxyalkyl, C₁-C₆carboxyalkyl, alkoxycarbonyl, aminoalkyl, optionally substituted C₃-C₇cycloalkyl, optionally substituted aryl, optionally substituted arylC₁-C₆ alkyl, aryloxy, optionally substituted heteroalicyclic, oroptionally substituted heteroaryl; where Formula VII is as follows:

R¹ is hydrogen, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₃-C₇ cycloalkyl, optionally substituted aryl, optionallysubstituted heteroalicyclic, optionally substitutedheteroalicyclicalkyl, optionally substituted heteroaryl or optionallysubstituted heteroarylalkyl; X is —NR³—; R³ is hydrogen; R⁴ isoptionally substituted C₁-C₆ alkyl; R⁵ is hydrogen; R⁶ is acyl and R² isheterocyclyl-aryl-optionally substituted with 1, 2, 3, or 4 R⁸ groups;or R⁶ is halo and R² is optionally substituted C₁-C₆ alkyl, C₃-C₇cycloalkyl, phenyl, aryl-C₁₋₆ alkyl, heteroalicyclicalkyl, orheterocyclyl-aryl-; where the C₃-C₇ cycloalkyl, phenyl, phenyl,aryl-C₁₋₆ alkyl, heteroalicyclicalkyl, and heterocyclyl-aryl-groups inR² are optionally substituted with 1, 2, 3, or 4 R⁸ groups; or R⁶ isphenyl optionally substituted with 1, 2, or 3 halo; and R² is phenyl orheterocyclyl-aryl-; where the phenyl and heterocyclyl-aryl-groups in R²are optionally substituted with 1, 2, 3, or 4 R⁸ groups; or R⁶ isheteroaryl optionally substituted with 1, 2, or 3 halo; and R² isheterocyclyl-aryl-optionally substituted with 1, 2, 3, 4, or 5 R⁸groups; each R⁸ at each instance is independently hydroxy, halo, C₁-C₆alkyl, haloalkyl, optionally substituted C₁-C₆ alkoxy, C₁-C₆alkoxyalkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkoxyalkylaminoalkyl,—O—C₁-C₆alkylheterocyclyl, aminoalkyl, optionally substituted C₃-C₇cycloalkyl, optionally substituted aryl, optionally substituted arylC₁-C₆ alkyl, optionally substituted heteroalicyclic, optionallysubstituted heteroalicyclicalkyl, optionally substituted heteroaryl oroptionally substituted heteroarylalkyl; where Formula VIIIa is asfollows:

or a pharmaceutically acceptable salt or solvate thereof, wherein W¹,W², W³, and W⁴ are —C(R₁)— or W² and W³ are —C(R₁)— and one of W¹ and W⁴is —N— and the other is —C(R₁)—; X is —N(R₅)—; A is aryl, heteroaryl, orheterocycloalkyl where the aryl, heteroaryl, and heterocycloalkyl areoptionally substituted with (R₂)_(n1); or B is aryl, —C₁-C₆ alkylaryl,heteroaryl, or heterocycloalkyl, where the aryl, C₁-C₆-alkyl,heteroaryl, and heterocycloalkyl are independently optionallysubstituted with (R₃)_(n2); n1 is 0, 1, 2, or 3; n2 is or an integerfrom 1 to 5; each R₁ is independently hydrogen, C₁-C₆-alkyl, haloalkyl,C₁-C₆-alkoxy, haloalkoxy, or —NO₂; each R₂ (when R₂ is present) isindependently —C₁-C₆-alkanyl, —C₁-C₆-alkenyl, —OR₆, —N(R₇)—C(O)—R₆,—N(R₇)—C(O)—C₀-C₆ alkyl-N(R_(7b))R_(7a), —OC(O)—C₀-C₆ alkyl-N(R₇)R_(7a),—C₀-C₆alkyl-C(O)R₆, heterocycloalkyl, aryl, halo, —NO₂, or—C₀-C₆-alkyl-N(R₇)R_(7a), wherein each alkyl, aryl, and heterocycloalkylgroups, each either alone or as part of another group within R₂, isindependently optionally substituted with one, two, three, four, or fivegroups selected from C₁-C₆-alkyl, C₁-C₆-alkoxy, halo, haloalkyl, andhaloalkoxy; each R₃ (when R₃ is present) is independently hydroxy, —NO₂,halo, —CN, C₁-C₆-alkanyl, C₂-C₆-alkenyl, C₁-C₆ alkoxy, —C₀-C₆alkyl-N(R₇)C(O)—C₀-C₆-alkyl-N(R_(7b))R_(7a),—C₀-C₆-alkyl-N(R₇)C(O)—C₀-C₆-alkyl-N(R_(7b))C(O)R_(7a), —C₀-C₆alkyl-C(O)N(R₇)—C₀-C₆-alkyl-N(R₇)R_(7a),—C₀-C₆-alkyl-C(O)N(R₇)—C₁-C₆-alkyl-C(O)OR_(7a),—C₀-C₆-alkyl-N(R₇)—C(O)—C₀-C₆-alkyl-(R₇),—C₀-C₆-alkyl-N(R₇)—C₀-C₆-alkyl-N(R₇)R_(7a),—C₀-C₆-alkyl-N(R₇)C(O)—C₀-C₆-alkyl-N(R_(7b))—C₀-C₆-alkyl-N(R_(7c))R_(7a),—C₀-C₆-alkyl-N(R₇)C(O)O—C₀-C₆-alkyl-N(R_(7b))R_(7a),—C₀-C₆-alkyl-N(R₇)—C₀-C₆ alkyl-C(═N(R_(7b))(R_(7a)))(NR_(7c)R_(7d)),—C₀-C₆-alkyl-heteroaryl, —C₀-C₆-alkyl-OR₆, —CO₀C₆-alkyl-C(O)OR₆,—C₀-C₆-alkyl-N(R₇)R_(7a), —C₀-C₆-alkyl-C(O)—NR₇R_(7a),—C₀-C₆-alkyl-C(O)—R₇, —S(O)₂R₇, —SO₂N(R₇)—C₀-C₆-alkyl-N(R₇)R_(7a),—C₀-C₆-alkyl-C(O)-heterocycloalkyl (dupe of C(O)R7),—C₀-C₆-alkyl-C(O)N(R₇)—C₀-C₆-alkyl-heterocycloalkyl,—C₀-C₆-alkyl-N(R₇)C(O)—C₀-C₆-alkyl-cycloalkyl,—C₀-C₆-alkyl-N(R₇)—C(O)—C₀-C₆-alkyl-aryl,—C₀-C₆-alkyl-N(R₇)—C(O)—C₀-C₆-alkyl-heteroaryl,—C₀-C₆-alkyl-N(R₇)C(O)—C₀-C₆-alkyl-heterocycloalkyl,—C₀-C₆-alkyl-N(R₇)C(O)—C₀-C₆-alkyl-heterocycloalkyl-aryl, or—N(R₇)C(O)R_(7a), wherein each of the alkyl, alkanyl, alkenyl,cycloalkyl, aryl, alkoxy, heterocycloalkyl, and heteroaryl groups,either alone or as part of another group within R₃, is independentlyoptionally substituted with 1, 2, 3, 4, or 5 groups selected fromC₁-C₆-alkanyl, C₁-C₆ alkenyl, cycloalkyl, halo, —C(O)—R₆, oxo, hydroxy,—C₀-C₆-alkyl-N(R₈)R_(8a), —C₀-C₆-alkyl-heterocycloalkyl,—C₀-C₆-alkyl-aryl, —C₀-C₆-alkyl-heteroaryl, —C(O)OR₆, and hydroxyalkyl;R₄ is hydrogen; R₅ is hydrogen; R₆ and R₉ are independently hydrogen,C₁-C₆-alkyl, aryl, arylalkyl, or cycloalkyl, where each of the—C₁-C₆-alkyl, aryl, arylalkyl, and cycloalkyl, is independentlyoptionally substituted with 1, 2, 3, 4, or 5 groups selected fromC₁-C₆-alkoxy, C₁-C₆-alkyl, and halo; and R₇, R_(7a) R_(7b), R_(7c), andR_(7d) are independently hydrogen, —C₁-C₆-alkanyl, —C₁-C₆-alkenyl, —OH,—O—C₁-C₆ alkanyl, —O—C₁-C₆ alkenyl, —O—C₀-C₆-alkyl-aryl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, or heterocycloalkylalkyl, wherein each of the alkyl,aryl, heteroaryl, and heterocycloalkyl, either alone or part of anothergroup within R₇, R_(7a) R_(7b), R_(7c), and R_(7d), is independentlyoptionally substituted with 1, 2, 3, 4, or 5 —NH₂, alkylamino,dialkylamino, —S—C₁-C₆-alkyl, —CN, hydroxy, oxo, C₁-C₆ alkoxy, C₁-C₆alkyl, or halo; and where Formula VIIIb is as follows:

or a pharmaceutically acceptable salt or solvate thereof, wherein n1 isone or two; and n2 is one or two; n3 is 0, 1, or two; each R₁ isindependently hydrogen, C₁-C₆-alkyl, haloalkyl, C₁-C₆-alkoxy,haloalkoxy, —NO₂, halo, hydroxy, hydroxyalkyl, —CN, cyanoalkyl, or—C₀-C₆ alkyl-N(R₁₀)R_(10a) where R₁₀ and R_(10a) are independentlyhydrogen, —C₁-C₆-alkyl, —OH, —O—C₁-C₆ alkyl, haloalkyl, or haloalkoxy;each R₂ (when R₂ is present) is independently C₁-C₆-alkanyl,C₁-C₆-alkenyl, —OR₆, —N(R₇)—C(O)—R₆, —N(R₇)—C(O)—C₀-C₆alkyl-N(R_(7b))R_(7a), —OC(O)—C₀-C₆ alkyl-N(R₇)R_(7a),—C₀-C₆alkyl-C(O)R₆, heterocycloalkyl, aryl, halo, —NO₂, or—C₀-C₆-alkyl-N(R₇)R_(7a), wherein each alkyl, aryl, and heterocycloalkylgroups, each either alone or as part of another group within R₂, isindependently optionally substituted with one, two, three, four, or fivegroups selected from C₁-C₆-alkyl, C₁-C₆-alkoxy, halo, haloalkyl, andhaloalkoxy; each R₃ (when R₃ is present) is independently hydroxy, —NO₂,halo, —CN, C₁-C₆-alkanyl, C₂-C₆-alkenyl, C₁-C₆ alkoxy, —C₀-C₆alkyl-N(R₇)C(O)—C₀-C₆-alkyl-N(R_(7b))R_(7a),—C₀-C₆-alkyl-N(R₇)C(O)—C₀-C₆-alkyl-N(R_(7b))C(O)R_(7a), —C₀-C₆alkyl-C(O)N(R₇)—C₀-C₆-alkyl-N(R₇)R_(7a),—C₀-C₆-alkyl-C(O)N(R₇)—C₁-C₆-alkyl-C(O)OR_(7a),—C₀-C₆-alkyl-N(R₇)—C(O)—C₀-C₆-alkyl-(R₇),—C₀-C₆-alkyl-N(R₇)—C₀-C₆-alkyl-N(R₇)R_(7a),—C₀-C₆-alkyl-N(R₇)C(O)—C₀-C₆-alkyl-N(R_(7b))—C₀-C₆-alkyl-N(R_(7c))R_(7a),—C₀-C₆-alkyl-N(R₇)C(O)O—C₀-C₆-alkyl-N(R_(7b))R_(7a),—C₀-C₆-alkyl-N(R₇)—C₀-C₆ alkyl-C(═N(R_(7b))(R_(7a)))(NR_(7c)R_(7d)),—C₀-C₆-alkyl-heteroaryl, —C₀-C₆-alkyl-OR₆, —C₀-C₆-alkyl-C(O)OR₆,—C₀-C₆-alkyl-N(R₇)R_(7a), —C₀-C₆-alkyl-C(O)—NR₇R_(7a),—C₀-C₆-alkyl-C(O)—R₇, —S(O)₂R₇, —SO₂N(R₇)—C₀-C₆-alkyl-N(R₇)R_(7a),—C₀-C₆-alkyl-C(O)-heterocycloalkyl (dupe of C(O)R7),—C₀-C₆-alkyl-C(O)N(R₇)—C₀-C₆-alkyl-heterocycloalkyl,—C₀-C₆-alkyl-N(R₇)C(O)—C₀-C₆-alkyl-cycloalkyl,—C₀-C₆-alkyl-N(R₇)—C(O)—C₀-C₆-alkyl-aryl,—C₀-C₆-alkyl-N(R₇)—C(O)—C₀-C₆-alkyl-heteroaryl,—C₀-C₆-alkyl-N(R₇)C(O)—C₀-C₆-alkyl-heterocycloalkyl,—C₀-C₆-alkyl-N(R₇)C(O)—C₀-C₆-alkyl-heterocycloalkyl-aryl, or—N(R₇)C(O)R_(7a), wherein each of the alkyl, alkanyl, alkenyl,cycloalkyl, aryl, alkoxy, heterocycloalkyl, and heteroaryl groups,either alone or as part of another group within R₃, is independentlyoptionally substituted with 1, 2, 3, 4, or 5 groups selected fromC₁-C₆-alkanyl, C₁-C₆ alkenyl, cycloalkyl, halo, —C(O)—R₆, oxo, hydroxy,—C₀-C₆-alkyl-N(R₈)R_(8a), —C₀-C₆-alkyl-heterocycloalkyl,—C₀-C₆-alkyl-aryl, —C₀-C₆-alkyl-heteroaryl, —C(O)OR₆, and hydroxyalkyl;R₄ is hydrogen; R₅ is hydrogen; R₆ is hydrogen, C₁-C₆-alkyl, aryl,arylalkyl, or cycloalkyl, where each of the —C₁-C₆-alkyl, aryl,arylalkyl, and cycloalkyl, is independently optionally substituted with1, 2, 3, 4, or 5 groups selected from C₁-C₆-alkoxy, C₁-C₆-alkyl, andhalo; and R₇, R_(7a) R_(7b), R_(7c), and R_(7d) are independentlyhydrogen, —C₁-C₆-alkanyl, —C₁-C₆-alkenyl, —OH, —O—C₁-C₆ alkanyl,—O—C₁-C₆ alkenyl, —O—C₀-C₆-alkyl-aryl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, orheterocycloalkylalkyl, wherein each of the alkyl, aryl, heteroaryl, andheterocycloalkyl, either alone or part of another group within R₇,R_(7a) R_(7b), R_(7c), and R_(7d), is independently optionallysubstituted with 1, 2, 3, 4, or 5 —NH₂, alkylamino, dialkylamino,—S—C₁-C₆-alkyl, —CN, hydroxy, oxo, C₁-C₆ alkoxy, C₁-C₆ alkyl, or halo.2. The method of claim 1 wherein the cancer is melanoma, bladder cancer,Wilm's cancer, ovarian cancer, pancreatic cancer, gastrointestinalstroma cancer, breast cancer, prostate cancer, bone cancer, small celllung cancer, non-small cell lung cancer, colorectal cancer, cervicalcancer, endometrium cancer, synovial sarcoma, vasoactive intestinalpeptide secreting tumors, acute myelogenous leukemia (AML), acutelymphocytic leukemia (ALL), Philadelphia Chromosome-Associated AcuteLymphoblastic Leukemia (Ph+ ALL), chronic lymphocytic leukemia (CLL), orchronic myelogenous leukemia (CML).
 3. The method of claim 2, whereinthe cancer is melanoma.
 4. The method of claim 2, wherein the cancer isfurther characterized by having a mutation in the B-RAF gene.
 5. Themethod of claim 4, wherein the mutation in B-RAF is an activatingmutation.
 6. The method of claim 2, wherein the cancer is furthercharacterized by having a mutation in the PTEN gene.
 7. The method ofclaim 6, wherein the mutation eliminates PTEN function.
 8. The method ofclaim 7, wherein the cancer also contains a mutation in the B-RAF geneand wherein the mutation is an activating mutation.
 9. The method ofclaim 1 where the cancer is mediated, at least in part, by inhibitingMEK and PI3K.
 10. The method of claims 1, 2, 3, 4, 5, 6, 7, 8, or 9,wherein the MEK Compound is selected from:1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-one;6-(azetidin-1-ylcarbonyl)-2,3-difluoro-N-(2-fluoro-4-iodophenyl)aniline;6-[(3,3-difluoroazetidin-1-yl)carbonyl]-2,3-difluoro-N-(2-fluoro-4-iodophenyl)aniline;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(hydroxymethyl)azetidin-3-ol;2,3-difluoro-N-(2-fluoro-4-iodophenyl)-6-{[3-(methyloxy)azetidin-1-yl]carbonyl}aniline;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(trifluoromethyl)azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-prop-2-en-1-ylazetidin-3-ol;3-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]propane-1,2-diol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-ethylazetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-methylazetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidine-2-carboxylicacid;[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-2-yl]methanol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-ethenylazetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidine-3-carboxylicacid;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-oneoxime;[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]methanol;1-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]ethane-1,2-diol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-amine;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidine-3-carboxamide;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N-hydroxyazetidine-3-carboxamide;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidine-2-carboxamide;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N-hydroxyazetidine-2-carboxamide;N-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]methanesulfonamide;N-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]acetamide;1,1-dimethylethyl[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]carbamate;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(pyrrolidin-1-ylmethyl)azetidin-3-ol;3-[(diethylamino)methyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(dimethylamino)methyl]azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N-methyl-N-prop-2-en-1-ylazetidine-3-carboxamide;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N-methylazetidine-3-carboxamide;N-butyl-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidine-3-carboxamide;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N-prop-2-en-1-ylazetidine-3-carboxamide;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N-ethyl-N-(2-hydroxyethyl)azetidine-3-carboxamide;N-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]-2-methylpropanamide;N-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]formamide;N-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]-3,4-dihydroxybutanamide;methyl[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]carbamate;N-butyl-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-amine;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-N,N-diprop-2-en-1-ylazetidin-3-amine;1-({4-[(2-fluoro-4-iodophenyl)amino]-3-thienyl}carbonyl)azetidin-3-amine;1-({4-[(2-fluoro-4-iodophenyl)amino]-3-thienyl}carbonyl)azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2R)-piperidin-2-yl]azetidin-3-ol;1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[2-pyrrolidin-2-yl]azetidin-3-ol;3-(aminomethyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol;3-[1-aminoethyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol;and3-[1-aminopropyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol.11. The method of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 wherein thePI3K Compound is selected from:6-bromo-8-ethyl-4-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one;6-bromo-8-ethyl-4-methyl-2-[(phenylmethyl)amino]pyrido[2,3-d]pyrimidin-7(8H)-one;6-bromo-8-ethyl-4-methyl-2-(phenylamino)pyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-2-(ethylamino)-4-methyl-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one;6-bromo-8-ethyl-4-methyl-2-[(1-methylethyl)amino]pyrido[2,3-d]pyrimidin-7(8H)-one;6-bromo-2-[(1,1-dimethylethyl)amino]-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;6-bromo-2-(cyclopentylamino)-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-4-methyl-6-phenyl-2-(phenylamino)pyrido[2,3-d]pyrimidin-7(8H)-one;6-biphenyl-4-yl-8-ethyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;6-(2,4-difluorophenyl)-8-ethyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;6-(3-chloro-4-fluorophenyl)-8-ethyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-2-(ethylamino)-4-methyl-6-[4-(methyloxy)phenyl]pyrido[2,3-d]pyrimidin-7(8H)-one;6-(2,4-dichlorophenyl)-8-ethyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;6-(3,4-difluorophenyl)-8-ethyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-2-(ethylamino)-4-methyl-6-[2-(methyloxy)phenyl]pyrido[2,3-d]pyrimidin-7(8H)-one;6-bromo-2-(cyclohexylamino)-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;6-bromo-8-ethyl-4-methyl-2-[(2-morpholin-4-ylethyl)amino]pyrido[2,3-d]pyrimidin-7(8H)-one;6-bromo-8-ethyl-4-methyl-2-[(3-morpholin-4-ylpropyl)amino]pyrido[2,3-d]pyrimidin-7(8H)-one;6-bromo-2-{[3-(dimethylamino)propyl]amino}-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-2-(ethylamino)-4-methyl-6-[4-(phenyloxy)phenyl]pyrido[2,3-d]pyrimidin-7(8H)-one;6-[2,4-bis(methyloxy)phenyl]-8-ethyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;6-bromo-8-ethyl-2-[(2-fluorophenyl)amino]-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-2-(ethylamino)-6-(3-fluorophenyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-2-(ethylamino)-6-(2-fluorophenyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-2-(ethylamino)-4-methyl-6-[3-(trifluoromethyl)phenyl]pyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-2-(ethylamino)-6-(4-fluorophenyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-2-(ethylamino)-4-methyl-6-(2-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-2-(ethylamino)-4-methyl-6-[3-(methyloxy)phenyl]pyrido[2,3-d]pyrimidin-7(8H)-one;6-(3-chlorophenyl)-8-ethyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;6-bromo-8-ethyl-4-methyl-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one;6-(4-chlorophenyl)-8-ethyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-2-(ethylamino)-4-methyl-6-(3-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-2-(ethylamino)-4-methyl-6-(4-methyl-2-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-2-(ethylamino)-4-methyl-6-(4-methyl-3-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one;1,1-dimethylethyl2-[8-ethyl-2-(ethylamino)-4-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl]-1H-pyrrole-1-carboxylate;6-bromo-8-ethyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;6-bromo-8-ethyl-4-methyl-2-[(4-morpholin-4-ylphenyl)amino]pyrido[2,3-d]pyrimidin-7(8H)-one;6-bromo-8-ethyl-4-methyl-2-({4-[4-(phenylmethyl)piperazin-1-yl]phenyl}amino)pyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-2-(ethylamino)-4-methyl-6-(1H-pyrrol-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;6-(5-chloro-2-thienyl)-8-ethyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-4-methyl-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-6-(2-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-2-(ethylamino)-4-methyl-6-pyrimidin-5-ylpyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-2-(ethylamino)-6-(3-fluoropyridin-4-yl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-2-(ethylamino)-6-furan-3-yl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-2-(ethylamino)-4-methyl-6-[1-(phenylmethyl)-1H-pyrazol-4-yl]pyrido[2,3-d]pyrimidin-7(8H)-one;6-(3,5-dimethylisoxazol-4-yl)-8-ethyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-4-methyl-2-({4-[4-(phenylmethyl)piperazin-1-yl]phenyl}amino)-6-(2-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one;6-bromo-2-(ethylamino)-4-methyl-8-(1-methylethyl)pyrido[2,3-d]pyrimidin-7(8H)-one;2-(ethylamino)-4-methyl-8-(1-methylethyl)-6-(2-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-6-(2-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-2-(ethylamino)-6-(1H-indol-6-yl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-2-(ethylamino)-4-methyl-6-(5-phenyl-2-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one;2-(ethylamino)-6-furan-3-yl-4-methyl-8-(1-methylethyl)pyrido[2,3-d]pyrimidin-7(8H)-one;6-bromo-8-ethyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-2-(ethylamino)pyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-2-(ethylamino)-4-methyl-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one;6-bromo-8-ethyl-2-(ethylamino)pyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-2-(ethylamino)-4-methyl-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-6-furan-3-yl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one;2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-8-(1-methylethyl)-6-(2-thienyl)pyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-6-(3-fluorophenyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-8-(1-methylethyl)-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one;2-[(4-{[2-(diethylamino)ethyl]oxy}phenyl)amino]-8-ethyl-4-methyl-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-2-[(4-hydroxyphenyl)amino]-4-methyl-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one;8-cyclohexyl-2-(ethylamino)-4-methyl-6-(2-thienylpyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;6-(3,5-difluorophenyl)-8-ethyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-4-methyl-6-phenyl-2-({4-[(2-piperidin-1-ylethyl)oxy]phenyl}amino)pyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-4-methyl-2-({4-[(2-morpholin-4-ylethyl)oxy]phenyl}amino)-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one;6-bromo-2-(ethylamino)-4-methyl-8-[3-(methyloxy)propyl]pyrido[2,3-d]pyrimidin-7(8H)-one;6-bromo-2-(ethylamino)-8-[2-(ethyloxy)ethyl]-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;6-bromo-2-(ethylamino)-4-methyl-8-(2-piperidin-1-ylethyl)pyrido[2,3-d]pyrimidin-7(8H)-one;6-bromo-2-(ethylamino)-8-[3-(ethyloxy)propyl]-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;6-bromo-2-(ethylamino)-4-methyl-8-{3-[(1-methylethyl)oxy]propyl}pyrido[2,3-d]pyrimidin-7(8H)-one;6-bromo-2-(ethylamino)-8-(3-hydroxypropyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;6-bromo-2-(ethylamino)-8-(2-hydroxyethyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;6-bromo-8-cyclopropyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;6-bromo-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-8-(1-methylethyl)pyrido[2,3-d]pyrimidin-7(8H)-one;2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-8-(1-methylethyl)-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;6-acetyl-8-ethyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-2-(ethylamino)-4-methyl-6-(1,3-thiazol-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;6-bromo-8-cyclopentyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;8-cyclopentyl-2-(ethylamino)-4-methyl-6-(1H-pyrazol-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;cyclopentyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;2-(ethylamino)-4-methyl-8-(1-methylethyl)-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-2-(ethylamino)-4-methyl-6-(1H-pyrazol-1-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;2-(ethylamino)-4-methyl-8-(1-methylethyl)-6-(1H-pyrazol-1-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;8-cyclopentyl-2-(ethylamino)-4-methyl-6-(1H-pyrazol-1-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-6-(1H-pyrazol-1-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-8-(1-methylethyl)-6-(1H-pyrazol-1-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;8-cyclopentyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-6-(1H-pyrazol-1-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;8-cyclopentyl-2-(ethylamino)-4-methyl-6-(1H-pyrazol-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;2-(ethylamino)-4-methyl-8-(1-methylethyl)-6-(1H-pyrazol-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;1,1-dimethylethyl4-{4-[(6-bromo-8-ethyl-4-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino]phenyl}piperazine-1-carboxylate;6-bromo-8-ethyl-4-methyl-2-[(4-piperazin-1-ylphenyl)amino]pyrido[2,3-d]pyrimidin-7(8H)-one;8-cyclopentyl-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-4-methyl-6-(1H-pyrazol-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;8-cyclopentyl-2-[(4-fluorophenyl)amino]-4-methyl-6-(1H-pyrazol-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;6-bromo-8-ethyl-2-[(4-fluorophenyl)amino]-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-4-methyl-6-(1H-pyrazol-5-yl)-2-[(2,2,2-trifluoroethyl)amino]pyrido[2,3-d]pyrimidin-7(8H)-one;6-bromo-8-cyclopentyl-2-[(4-hydroxyphenyl)amino]-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one;2-amino-8-ethyl-4-methyl-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;2-(ethylamino)-4-methyl-6-(1H-pyrazol-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;6-bromo-8-cyclopentyl-4-methyl-2-({4-[(2-piperidin-1-ylethyl)oxy]phenyl}amino)pyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-4-methyl-2-(methylamino)-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;8-cyclopentyl-4-methyl-2-(phenylamino)-6-(1H-pyrazol-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;1,1-dimethylethyl4-(4-{[8-cyclopentyl-4-methyl-7-oxo-6-(1H-pyrazol-5-yl)-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}phenyl)piperazine-1-carboxylate;8-cyclopentyl-4-methyl-2-[(4-piperazin-1-ylphenyl)amino]-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;2-amino-8-cyclopentyl-4-methyl-6-(1H-pyrazol-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;8-ethyl-2-[(2-fluoroethyl)amino]-4-methyl-6-(1H-pyrazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;2-amino-4-methyl-8-(1-methylethyl)-6-(1H-pyrazol-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one;and8-cyclopentyl-4-methyl-2-({4-[(2-piperidin-1-ylethyl)oxy]phenyl}amino)-6-(1H-pyrazol-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one.12. The method of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 wherein thePI3K Compound is selected from:4-chloro-N-{3-[(3-chloro-4-piperidin-1-ylphenyl)amino]-6-methylquinoxalin-2-yl}benzenesulfonamide;N-(3-{[2-(ethyloxy)phenyl]amino}quinoxalin-2-yl)-4-methylbenzenesulfonamide;N-(3-{[4-chloro-2,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide;N-[3-({2-[2,5-bis(methyloxy)phenyl]ethyl}amino)quinoxalin-2-yl]benzenesulfonamide;N-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide;N-(3-{[3,4,5-tris(methyloxy)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide;N-[3-({3-[(phenylmethyl)oxy]phenyl}amino)quinoxalin-2-yl]benzenesulfonamide;N-(3-{[3-(phenyloxy)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide;N-[3-(piperidin-1-ylamino)quinoxalin-2-yl]benzenesulfonamide;N-[3-(4-phenylpiperazin-1-yl)quinoxalin-2-yl]benzenesulfonamide;N-{3-[4-(phenylmethyl)piperidin-1-yl]quinoxalin-2-yl}benzenesulfonamide;N-{3-[(4-morpholin-4-ylphenyl)amino]quinoxalin-2-yl}benzenesulfonamide;N-(3-{[3-(methyloxy)-5-(trifluoromethyl)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide;N-(3-{[2,5-bis(ethyloxy)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide;N-(3-morpholin-4-ylquinoxalin-2-yl)benzenesulfonamide;N-(3-{[2,5-bis(methyloxy)phenyl]amino}pyrazin-2-yl)-4-chlorobenzenesulfonamide;N-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-4-methylbenzenesulfonamide;N-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-nitrobenzenesulfonamide;N-(3-azidoquinoxalin-2-yl)benzenesulfonamide;N-[3-({[2,5-bis(methyloxy)phenyl]methyl}amino)quinoxalin-2-yl]benzenesulfonamide;N-(3-{[2-methyl-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide;N-[3-(dimethylamino)quinoxalin-2-yl]benzenesulfonamide;N-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)naphthalene-2-sulfonamide;4-(3-Benzensulfonylamino-quinoxalin-2-yl)-piperazine-1-carboxylic acidtert-butyl ester;N-[3-(2-Chloro-5-methoxy-phenylamino)-quinoxalin-2-yl]-benzensulfonamide;3-amino-N-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide;N-(3-piperazin-1-ylquinoxalin-2-yl)benzenesulfonamide;N-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-4-chlorobenzenesulfonamide;N-(3-{4-[(9-oxo-9H-fluoren-1-yl)carbonyl]piperazin-1-yl}quinoxalin-2-yl)benzenesulfonamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)acetamide;N-(3-{[4-chloro-3-(methyloxy)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide;N-(3-{[4-fluoro-3-(methyloxy)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide;N-(3-{[2′-(methyloxy)biphenyl-4-yl]amino}quinoxalin-2-yl)benzenesulfonamide;N-(3-{[5-methyl-2-(methyloxy)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide;3-amino-N-(3-{[2,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide;N-(3-{[2,5-bis(methyloxy)phenyl]amino}-6,7-dimethylquinoxalin-2-yl)benzenesulfonamide;N-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-4-bromobenzenesulfonamide;N-(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-nitrobenzenesulfonamide;N-(3-{[5-chloro-2-(methyloxy)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide;N-(3-{[2-(methyloxy)-5-(trifluoromethyl)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide;N-(3-{[2-(methyloxy)biphenyl-4-yl]amino}quinoxalin-2-yl)benzenesulfonamide;3-amino-N-(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-,N-2-dimethylglycinamide;N-(3-{[2,5-bis(methyloxy)phenyl]amino}-7-methylquinoxalin-2-yl)benzenesulfonamide;N-(3-{[2,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-4-(methyloxy)benzenesulfonamide;N-(3-{[2,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-bromobenzenesulfonamide;N-(3-{[2,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-fluorobenzenesulfonamide;N-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-2-fluorobenzenesulfonamide;N-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-4-(methyloxy)benzenesulfonamide;N-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-bromobenzenesulfonamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-1-methylpiperidine-4-carboxamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-3-piperidin-1-ylpropanamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-4-(dimethylamino)butanamide;N-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-(hydroxyamino)benzenesulfonamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-morpholin-4-ylacetamide;N-(3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-4-methylphenyl)-N-2-methylglycinamide;N-(3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-4-methylphenyl)-L-alaninamide;N-(3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-4-methylphenyl)-2-methylalaninamide;N-(3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-4-methylphenyl)-N-2-N-2-dimethylglycinamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-D-alaninamide;N-(3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-methylglycinamide;N-(3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-4-methylphenyl)-D-alaninamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-methylglycinamide;N-(3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-L-alaninamide;N-(3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-D-alaninamide;N-(3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-methylalaninamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-methylalaninamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-4-methylphenyl)-N-2-,N-2-dimethylglycinamide;N-(3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-[2-(dimethylamino)ethyl]-N-2-methylglycinamide;(2S)-2-amino-N-(3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)butanamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-[2-(dimethylamino)ethyl]-N-2-methylglycinamide;N-(3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-,N-2-dimethylglycinamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-methyl-L-alaninamide;N-(3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)glycinamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)glycinamide;N-(2-chloro-5-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-methylglycinamide;2-(dimethylamino)-N-(3-(N-(3-(3-(2-(dimethylamino)acetamido)-5-methoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide;N-(3-{[(3-{[2-acetyl-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-,N-2-dimethylglycinamide;N-(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-(formylamino)benzenesulfonamide;N-(3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-ethylglycinamide;N-(5-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-2-methylphenyl)glycinamide;2-azetidin-1-yl-N-(3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)acetamide;N-(3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-L-prolinamide;N-(3-{[(3-{[2-bromo-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-methylglycinamide;N-2-,N-2-dimethyl-N-(3-{[(3-{[6-(methyloxy)quinolin-8-yl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)glycinamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-L-alaninamide;N-(3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-methyl-D-alaninamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-L-prolinamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-D-serinamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)azetidine-3-carboxamide;N-(3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-,2-dimethylalaninamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-methyl-D-alaninamide;N-(3-{[(3-{[2-bromo-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-,N-2-dimethylglycinamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-propylglycinamide;N-(3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-methyl-L-alaninamide;N-(5-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-2-methylphenyl)-beta-alaninamide;N-(3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)piperidine-3-carboxamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(4-methyl-1,4-diazepan-1-yl)acetamide;(2S)-2-amino-N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)butanamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-(2-hydroxypropyl)glycinamide;N-(3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-(2-fluoroethyl)glycinamide;3-amino-N-(2-{[3,5-bis(methyloxy)phenyl]amino}pyrido[2,3-b]pyrazin-3-yl)benzenesulfonamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-[(2-methylpropyl)oxy]glycinamide;1-amino-N-(3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)cyclopropanecarboxamide;N-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-(formylamino)benzenesulfonamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-(cyclopropylmethyl)glycinamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-D-prolinamide;N-(3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-[3-(dimethylamino)azetidin-1-yl]acetamide;N-(3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-D-prolinamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)piperidine-2-carboxamide;N-(3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)morpholine-4-carboxamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-pyrrolidin-1-ylacetamide;N-(3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-6-,N-6-dimethyl-L-lysinamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-ethyl-N-2-methylglycinamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(1H-imidazol-4-yl)acetamide;1-amino-N-(3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)cyclopentanecarboxamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-(2-methylpropyl)glycinamide;N-(3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-ethyl-N-2-methylglycinamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-1-(1H-imidazol-4-ylmethyl)azetidine-3-carboxamide;N-(5-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-2-methylphenyl)-N-2-,N-2-dimethylglycinamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-1-ethylazetidine-3-carboxamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-methyl-N-2-(1-methylpyrrolidin-3-yl)glycinamide;N-(3-{[(2-{[3,5-bis(methyloxy)phenyl]amino}pyrido[2,3-b]pyrazin-3-yl)amino]sulfonyl}phenyl)-N-2-[2-(dimethylamino)ethyl]-N-2-methylglycinamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-[(3S)-3-hydroxypyrrolidin-1-yl]acetamide;1-amino-N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)cyclobutanecarboxamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-butylglycinamide;N-(3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(3-piperidin-1-ylazetidin-1-yl)acetamide;3-[(aminocarbonyl)amino]-N-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-1-hydroxycyclopropanecarboxamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(2,2-dimethylhydrazino)acetamide;N-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-[({[2-(dimethylamino)ethyl]amino}carbonyl)amino]benzenesulfonamide;N-(3-{[(3-{[3-fluoro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-methylglycinamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-hydroxyacetamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)pyridazine-4-carboxamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-(1-methylethyl)glycinamide;1-amino-N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)cyclopentanecarboxamide;1-amino-N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)cyclopropanecarboxamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-[3-(dimethylamino)pyrrolidin-1-yl]acetamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-[2-(dimethylamino)ethyl]glycinamide;2-(dimethylamino)ethyl(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)carbamate;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-1-(cyclopropylmethyl)azetidine-3-carboxamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-(1,1-dimethylethyl)glycinamide;N-2-methyl-N-(3-{[(3-{[3-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)glycinamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-1H-imidazole-2-carboxamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)isoxazole-5-carboxamide;N-(3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-(2,2,2-trifluoroethyl)glycinamide;3-amino-N-(3-{[2-methyl-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-3-oxocyclopentanecarboxamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-6-hydroxypyridine-2-carboxamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-(3-fluoro-4-hydroxyphenyl)glycinamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-1-(furan-2-ylmethyl)azetidine-3-carboxamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)pyrimidine-5-carboxamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-1H-pyrrole-2-carboxamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-methyl-N-2-(1-methylethyl)glycinamide;N-(3-{[(3-{[3-fluoro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-,N-2-dimethylglycinamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-1H-imidazole-4-carboxamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-,N-2-diethylglycinamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(3-methylisoxazol-5-yl)acetamide;N-2-,N-2-dimethyl-N-(3-{[(3-{[2-methyl-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)glycinamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-[(3-hydroxyphenyl)methyl]glycinamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-1-methyl-1H-pyrrole-2-carboxamide;4-amino-N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)tetrahydro-2H-pyran-4-carboxamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-[4-(methylamino)piperidin-1-yl]acetamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-piperidin-1-ylacetamide;N-(4-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-,N-2-dimethylglycinamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-1-methyl-L-prolinamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)thiophene-3-carboxamide;3-amino-N-{3-[(2-chloro-5-hydroxyphenyl)amino]quinoxalin-2-yl}benzenesulfonamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-1-(cyclopropylcarbonyl)azetidine-3-carboxamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(4-methylpiperazin-1-yl)acetamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-1-(phenylmethyl)azetidine-3-carboxamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-chloropyridine-3-carboxamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-pyridin-4-ylacetamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-methyl-N-2-prop-2-en-1-ylglycinamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-(phenylmethyl)glycinamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(methyloxy)acetamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-1-propanoylazetidine-3-carboxamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)pyridine-3-carboxamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-[2-(methyloxy)ethyl]glycinamide;1-acetyl-N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)piperidine-4-carboxamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(2-methylpyrrolidin-1-yl)acetamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)furan-3-carboxamide;N-2-,N-2-dimethyl-N-(3-{[(3-{[3-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)glycinamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-6-chloropyridine-3-carboxamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-chlorobenzamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-pyridin-2-ylacetamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-[3-(dimethylamino)azetidin-1-yl]acetamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-pyridin-3-ylacetamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(2-chlorophenyl)acetamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-[3-(dimethylamino)propyl]-N-2-methylglycinamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-ethyl-N-2-(2-hydroxyethyl)glycinamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-[2-(phenylmethyl)pyrrolidin-1-yl]acetamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)propanamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)furan-2-carboxamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-chloropyridine-4-carboxamide;N-2-acetyl-N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)glycinamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)butanamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-4-chlorobenzamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-4-methylbenzamide;1,1-dimethylethyl{2-[(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)amino]-2-oxoethyl}carbamate;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-1,3-benzodioxole-5-carboxamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-({[2-(methyloxy)phenyl]methyl}oxy)glycinamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)pyridine-4-carboxamide;N-(3-{[(3-{[4-fluoro-3-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-,N-2-dimethylglycinamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-[4-(3,4-dichlorophenyl)piperazin-1-yl]acetamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-3-pyridin-3-ylpropanamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)tetrahydrofuran-3-carboxamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-[(2-methylphenyl)methyl]glycinamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-methylbutanamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(3-fluorophenyl)acetamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-(1-methyl-1-phenylethyl)glycinamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-methylcyclopropanecarboxamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-methyl-4-(methyloxy)benzamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-methylpyridine-3-carboxamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-4-(methyloxy)benzamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(4-ethylpiperazin-1-yl)acetamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)thiophene-2-carboxamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-3-fluoro-2-methylbenzamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-bromothiophene-3-carboxamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-4-fluorobenzamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(3-methylpiperidin-1-yl)acetamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-methylpropanamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)pentanamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(ethyloxy)acetamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-(2-fluorophenyl)glycinamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-3-(dimethylamino)benzamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(4-methylpiperidin-1-yl)acetamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-(2-propylphenyl)glycinamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)benzamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)pyrazine-2-carboxamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-3-fluoro-4-(methyloxy)benzamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2,2-dimethylbutanamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-[(4-fluorophenyl)oxy]acetamide;1-acetyl-N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)azetidine-3-carboxamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-(4-methylphenyl)glycinamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-phenylglycinamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(4-prop-2-en-1-ylpiperazin-1-yl)acetamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-methylbenzamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-3-(methyloxy)propanamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-3-methylfuran-2-carboxamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2,2-dimethylpropanamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-[(phenylmethyl)oxy]glycinamide;N-{3-[({3-[(2-chloro-5-hydroxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]phenyl}-N-2-,N-2-dimethylglycinamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-(3-chlorophenyl)glycinamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)cyclobutanecarboxamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-[3-(methyloxy)phenyl]acetamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-1-methylcyclopropanecarboxamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-3-fluorobenzamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-4-(dimethylamino)benzamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-3,4-dichlorobenzamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-{[2-(methylthio)phenyl]methyl}glycinamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(2-fluorophenyl)acetamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-ethyl-N-2-(1-methylethyl)glycinamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-1,3-thiazole-4-carboxamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-methyl-N-2-(phenylmethyl)glycinamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-(2-thienylmethyl)glycinamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-(pyridin-2-ylmethyl)glycinamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-3-(methyloxy)benzamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-[(3-chloro-4-methylphenyl)methyl]glycinamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-methylpentanamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(4-chlorophenyl)acetamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-3-fluoro-4-methylbenzamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-[(2-methylphenyl)oxy]acetamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-cyclohexylacetamide;(1R,2R)-N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-phenylcyclopropanecarboxamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-3-chlorobenzamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-[2-(methyloxy)phenyl]acetamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-3-[3-(methyloxy)phenyl]propanamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-(2-fluoro-4-methylphenyl)glycinamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-[(3-fluorophenyl)methyl]glycinamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-[4-(methyloxy)phenyl]acetamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-phenylacetamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2,4-dichlorobenzamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-3-oxocyclohexanecarboxamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-(3-fluorophenyl)glycinamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(3-chlorophenyl)acetamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-(2-phenylpropyl)glycinamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-[(2,4-dimethylphenyl)methyl]glycinamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(2-methylpiperidin-1-yl)acetamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-[2-(methyloxy)phenyl]glycinamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(3,4-dihydroisoquinolin-2(1H)-yl)acetamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)pent-4-enamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-(2-methylphenyl)glycinamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(4-oxopiperidin-1-yl)acetamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-fluorobenzamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-(1-phenylethyl)glycinamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-fluoro-6-(methyloxy)benzamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-[2-(1-methylethyl)phenyl]glycinamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-3-[2-(methyloxy)phenyl]propanamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-4-methylpentanamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(2-phenylmorpholin-4-yl)acetamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-3-[4-(methyloxy)phenyl]propanamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-cyclopentyl-N-2-prop-2-en-1-ylglycinamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-methyl-N-2-[2-(methyloxy)ethyl]glycinamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-4-cyclopropyl-4-oxobutanamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-[3-(1,1-dimethylethyl)phenyl]glycinamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-(cyclopropylmethyl)-N-2-propylglycinamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(2-oxocyclopentyl)acetamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-(4-chlorophenyl)glycinamide;2-(1,4′-bipiperidin-1′-yl)-N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)acetamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(4-cyclopentylpiperazin-1-yl)acetamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(2-methylphenyl)acetamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-[(5-fluoro-2-methylphenyl)methyl]glycinamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-3,3-dimethylbutanamide;2-(2-chlorophenylamino)-N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)acetamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-5-fluoro-2-methylbenzamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-4-fluoro-3-methylbenzamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2,3-dichlorobenzamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(phenyloxy)acetamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-(2,3-dimethylphenyl)glycinamide;3-amino-N-(3-{[3,5-bis(methyloxy)phenyl]amino}pyrido[2,3-b]pyrazin-2-yl)benzenesulfonamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-fluoro-5-methylbenzamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-{[(4-methylphenyl)methyl]oxy}glycinamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-[4-(1-methylethyl)piperazin-1-yl]acetamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(4-fluorophenyl)acetamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-3-methylbutanamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-4-methyl-2-(methyloxy)benzamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(4-propylpiperidin-1-yl)acetamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-[(3-methylphenyl)oxy]acetamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)tetrahydrofuran-2-carboxamide;1,1-dimethylethyl2-{[(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)amino]carbonyl}piperidine-1-carboxylate;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-methyl-N-2-(pyridin-3-ylmethyl)glycinamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-ethyl-N-2-phenylglycinamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-{[2-(methyloxy)ethyl]oxy}acetamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-3-cyclopentylpropanamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2,5-dichlorobenzamide;2-(4-acetylpiperazin-1-yl)-N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)acetamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-5-fluoro-2-(methyloxy)benzamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-cyclohexyl-N-2-ethylglycinamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-5-methylisoxazole-3-carboxamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-3-methylpyridine-2-carboxamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(methyloxy)pyridine-3-carboxamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-3,5-dichlorobenzamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(1,3-thiazolidin-3-yl)acetamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(4-formylpiperazin-1-yl)acetamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(methyloxy)benzamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-methyl-N-2-(2-methylpropyl)glycinamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(4-formyl-1,4-diazepan-1-yl)acetamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-1-phenylcyclopropanecarboxamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(2,6-dimethylmorpholin-4-yl)acetamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(2-phenylpyrrolidin-1-yl)acetamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-(2,6-dimethylpiperidin-1-yl)acetamide;N-{3-[({3-[(4-chlorophenyl)amino]quinoxalin-2-yl}amino)sulfonyl]phenyl}-N-2-,N-2-dimethylglycinamide;N-{3-[({3-[(3-fluorophenyl)amino]quinoxalin-2-yl}amino)sulfonyl]phenyl}-N-2-,N-2-dimethylglycinamide;N-{3-[({3-[(3-chlorophenyl)amino]quinoxalin-2-yl}amino)sulfonyl]phenyl}-N-2-,N-2-dimethylglycinamide;3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-[2-(dimethylamino)-1-methylethyl]benzamide;3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-[2-(dimethylamino)ethyl]benzamide;5-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-[2-(dimethylamino)ethyl]-2-fluorobenzamide;3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-pyrrolidin-3-ylbenzamide;3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-[2-(dimethylamino)ethyl]benzamide;3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-(2-pyrrolidin-1-ylethyl)benzamide;N-(2-aminoethyl)-3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}benzamide;3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-[2-(dimethylamino)ethyl]-N-methylbenzamide;3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-(piperidin-2-ylmethyl)benzamide;3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-(1-methylazetidin-3-yl)benzamide;3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-(2-piperidin-1-ylethyl)benzamide;3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-[2-(diethylamino)ethyl]benzamide;3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-[2-(dimethylamino)ethyl]-N-methylbenzamide;3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-(1-methylpiperidin-3-yl)benzamide;3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-piperidin-3-ylbenzamide;3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-[(1-methylpiperidin-2-yl)methyl]benzamide;N-{2-[bis(2-hydroxyethyl)amino]ethyl}-3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}benzamide;3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-(1-ethylpiperidin-3-yl)benzamide;3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}benzamide;3-[(3-aminopyrrolidin-1-yl)carbonyl]-N-(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide;5-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-[2-(dimethylamino)ethyl]-2-(methyloxy)benzamide;N-(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-{[3-(methylamino)pyrrolidin-1-yl]carbonyl}benzenesulfonamide;3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}benzoicacid;3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-(2-morpholin-4-ylethyl)benzamide;3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-[(1-ethylpyrrolidin-2-yl)methyl]benzamide;3-[(4-amino-3-oxopyrazolidin-1-yl)carbonyl]-N-(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide;3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-methylbenzamide;3-[(3-aminoazetidin-1-yl)carbonyl]-N-(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide;3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-(pyridin-3-ylmethyl)benzamide;3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-(pyridin-2-ylmethyl)benzamide;3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-(2-hydroxyethyl)benzamide;3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-(3-oxopyrazolidin-4-yl)benzamide;3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-[2-(1H-imidazol-4-yl)ethyl]benzamide;N-(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-{[3-(dimethylamino)pyrrolidin-1-yl]carbonyl}benzenesulfonamide;3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-(pyridin-4-ylmethyl)benzamide;3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-methyl-N-(1-methylpyrrolidin-3-yl)benzamide;N-(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-{[3-(diethylamino)pyrrolidin-1-yl]carbonyl}benzenesulfonamide;3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-1H-pyrrol-1-ylbenzamide;3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-(3-pyrrolidin-1-ylpropyl)benzamide;3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-(2-cyanoethyl)-N-methylbenzamide;3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-[2-(methyloxy)ethyl]benzamide;3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-(2-cyanoethyl)-N-ethylbenzamide;3-[(3-aminopiperidin-1-yl)carbonyl]-N-(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide;3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}benzoicacid;3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-[3-(dimethylamino)propyl]benzamide;3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-morpholin-4-ylbenzamide;N-(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-[(2,2-dimethylhydrazino)carbonyl]benzenesulfonamide;3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-[3-(1H-imidazol-1-yl)propyl]benzamide;3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-[3-(diethylamino)propyl]benzamide;3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-(2-cyanoethyl)benzamide;methylN-[(3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)carbonyl]-beta-alaninate;3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-[2-(methylthio)ethyl]benzamide;3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-[2-(ethylthio)ethyl]benzamide;3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-[2-(ethylthio)ethyl]benzamide;3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-[2-(dimethylamino)ethyl]-N-ethylbenzamide;3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-[3-(2-oxopyrrolidin-1-yl)propyl]benzamide;3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-(2-pyridin-4-ylethyl)benzamide;3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-[3-(ethyloxy)propyl]benzamide;3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-(3-morpholin-4-ylpropyl)benzamide;3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-[3-(methyloxy)propyl]benzamide;3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-[3-(propyloxy)propyl]benzamide;3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-[3-(propyloxy)propyl]benzamide;ethylN-[(3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)carbonyl]-beta-alaninate;3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-{3-[(1-methylethyl)oxy]propyl}benzamide;3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-(1,1-dimethyl-2-piperidin-1-ylethyl)benzamide;3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-methyl-N-propylbenzamide;3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-piperidin-1-ylbenzamide;3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-[1-methyl-2-(methyloxy)ethyl]benzamide;3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-(1,1-dimethyl-2-morpholin-4-ylethyl)benzamide;N-(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-({2-[(dimethylamino)methyl]piperidin-1-yl}carbonyl)benzenesulfonamide;N-[3-(butyloxy)propyl]-3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}benzamide;3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-[4-(diethylamino)-1-methylbutyl]benzamide;3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-N-(1,1-dimethyl-2-oxo-2-piperidin-1-ylethyl)benzamide;N-(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-[(4-methylpiperazin-1-yl)carbonyl]benzenesulfonamide;N-(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-{[2-(piperidin-1-ylmethyl)piperidin-1-yl]carbonyl}benzenesulfonamide;N-(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)-6-oxo-1,6-dihydropyridine-3-sulfonamide;N-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-6-oxo-1,6-dihydropyridine-3-sulfonamide;3-amino-N-(3-{[6-(methyloxy)quinolin-8-yl]amino}quinoxalin-2-yl)benzenesulfonamide;N-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)thiophene-2-sulfonamide;N-(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-cyanobenzenesulfonamide;N-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-(methylamino)benzenesulfonamide;N-(2-{[3,5-bis(methyloxy)phenyl]amino}pyrido[2,3-b]pyrazin-3-yl)-3-nitrobenzenesulfonamide;N-(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-(1-{[2-(dimethylamino)ethyl]amino}ethyl)benzenesulfonamide;3-amino-N-(3-{[3-(methyloxy)-5-nitrophenyl]amino}quinoxalin-2-yl)benzenesulfonamide;3-acetyl-N-(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide;3-amino-N-(3-{[3-fluoro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide;N-(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)-N′-[2-(dimethylamino)ethyl]benzene-1,3-disulfonamide;N-(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)-N′-[3-(dimethylamino)propyl]benzene-1,3-disulfonamide;N-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-6-chloropyridine-3-sulfonamide;N-(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-{5-[(dimethylamino)methyl]-1,3,4-oxadiazol-2-yl}benzenesulfonamide;N-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-6-{[2-(dimethylamino)ethyl]amino}pyridine-3-sulfonamide;3-amino-N-(3-{[3-amino-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)benzenesulfonamide;N-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-(dimethylamino)benzenesulfonamide;N-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-6-{[2-(dimethylamino)ethyl]oxy}pyridine-3-sulfonamide;N-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-6-(dimethylamino)pyridine-3-sulfonamide;N-{3-[({3-[(4-fluorophenyl)amino]quinoxalin-2-yl}amino)sulfonyl]phenyl}-N-2-,N-2-dimethylglycinamide;N-(3-{[2-chloro-6-(methyloxy)pyridin-4-yl]amino}quinoxalin-2-yl)-3-nitrobenzenesulfonamide;N-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-4-cyanobenzenesulfonamide;N-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-4-fluorobenzenesulfonamide;N-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-4-fluoro-2-methylbenzenesulfonamide;N-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-2-methylbenzenesulfonamide;N-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-cyanobenzenesulfonamide;N-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-3,5-difluorobenzenesulfonamide;N-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-2-chlorobenzenesulfonamide;N-(4-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)acetamide;N-(3-{[6-(methyloxy)quinolin-8-yl]amino}quinoxalin-2-yl)-3-nitrobenzenesulfonamide;N-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-(2H-tetrazol-5-yl)benzenesulfonamide;N-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)naphthalene-1-sulfonamide;3-nitro-N-[3-(pyridin-4-ylamino)quinoxalin-2-yl]benzenesulfonamide;N-{3-[(2,6-dichloropyridin-4-yl)amino]quinoxalin-2-yl}-3-nitrobenzenesulfonamide;N-{3-[(2-chloropyridin-4-yl)amino]quinoxalin-2-yl}-3-nitrobenzenesulfonamide;N-(3-{[4,6-bis(methyloxy)pyrimidin-2-yl]amino}quinoxalin-2-yl)-3-nitrobenzenesulfonamide;N-(3-{[4-hydroxy-6-(methyloxy)pyrimidin-2-yl]amino}quinoxalin-2-yl)-3-nitrobenzenesulfonamide;N-{[(3-{[(3-{[2-chloro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}-4-methylphenyl)amino](dimethylamino)methylidene}-N-methylmethanaminium;N-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-fluorobenzenesulfonamide;N-(3-{[2-bromo-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-nitrobenzenesulfonamide;N-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-4-[(difluoromethyl)oxy]benzenesulfonamide;N-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-2-(trifluoromethyl)benzenesulfonamide;N-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-chloro-4-fluorobenzenesulfonamide;N-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-4-(trifluoromethyl)benzenesulfonamide;N-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-(methylsulfonyl)benzenesulfonamide;N-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-2,5-dichlorothiophene-3-sulfonamide;N-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-3,5-dichlorobenzenesulfonamide;N-(3-{[2-methyl-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-nitrobenzenesulfonamide;N-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-4-[(trifluoromethyl)oxy]benzenesulfonamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-2-[4-(dimethylamino)piperidin-1-yl]acetamide;N-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-5-chloro-2-(methyloxy)benzenesulfonamide;N-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-(trifluoromethyl)benzenesulfonamide;N-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-2,5-bis(methyloxy)benzenesulfonamide;N-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-3,5-dimethylisoxazole-4-sulfonamide;N-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-5-bromo-2-(methyloxy)benzenesulfonamide;N-(3-{[3-fluoro-5-(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-nitrobenzenesulfonamide;N-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-fluoro-4-methylbenzenesulfonamide;N-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-chloro-4-methylbenzenesulfonamide;N-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-2,5-dimethylthiophene-3-sulfonamide;N-(3-{[3-(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-nitrobenzenesulfonamide;N-{3-[(2-chloro-5-hydroxyphenyl)amino]quinoxalin-2-yl}-3-nitrobenzenesulfonamide;N-(3-{[(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-4-methyl-3-(methyloxy)benzamide;N-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-1-phenylmethanesulfonamide;N-(3-{[3-(methyloxy)-5-nitrophenyl]amino}quinoxalin-2-yl)-3-nitrobenzenesulfonamide;N-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-1-(3-chlorophenyl)methanesulfonamide;N-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-4,5-dichlorothiophene-2-sulfonamide;N-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonamide;N-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-3,5-bis(trifluoromethyl)benzenesulfonamide;N-{3-[(3-hydroxyphenyl)amino]quinoxalin-2-yl}-3-nitrobenzenesulfonamide;3-nitro-N-[3-({3-[(trifluoromethyl)oxy]phenyl}amino)quinoxalin-2-yl]benzenesulfonamide;3-nitro-N-[3-(pyridin-3-ylamino)quinoxalin-2-yl]benzenesulfonamide;N-[3-(morpholin-4-ylamino)quinoxalin-2-yl]-3-nitrobenzenesulfonamide;3-[(3-{[(3-nitrophenyl)sulfonyl]amino}quinoxalin-2-yl)amino]phenyldimethylcarbamate;N-{3-[(2-chloropyridin-3-yl)amino]quinoxalin-2-yl}-3-nitrobenzenesulfonamide;3-nitro-N-[3-(tetrahydro-2H-pyran-4-ylamino)quinoxalin-2-yl]benzenesulfonamide;N-{3-[(4-fluorophenyl)amino]quinoxalin-2-yl}benzenesulfonamide;N-[3-({3-[(1-methylethyl)oxy]phenyl}amino)quinoxalin-2-yl]-3-nitrobenzenesulfonamide;N-{3-[(3-hydroxy-2-methylphenyl)amino]quinoxalin-2-yl}-3-nitrobenzenesulfonamide;N-{3-[(2,5-difluorophenyl)amino]quinoxalin-2-yl}-3-nitrobenzenesulfonamide;N-[3-({3-[(difluoromethyl)oxy]phenyl}amino)quinoxalin-2-yl]-3-nitrobenzenesulfonamide;N-(3-{[2-(methyloxy)pyridin-3-yl]amino}quinoxalin-2-yl)-3-nitrobenzenesulfonamide;N-(3-{[3-(ethyloxy)phenyl]amino}quinoxalin-2-yl)-3-nitrobenzenesulfonamide;N-{3-[(2,2-difluoro-1,3-benzodioxol-4-yl)amino]quinoxalin-2-yl}-3-nitrobenzenesulfonamide;N-{3-[(3-{[(3-nitrophenyl)sulfonyl]amino}quinoxalin-2-yl)amino]phenyl}acetamide;N-[3-(4-amino-1H-indol-1-yl)quinoxalin-2-yl]-3-nitrobenzenesulfonamide;N-[3-(1H-indol-4-ylamino)quinoxalin-2-yl]-3-nitrobenzenesulfonamide;N-2-,N-2-dimethyl-N-(3-{[(3-{[4-(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)glycinamide;N-[3-(1H-indazol-6-ylamino)quinoxalin-2-yl]-3-nitrobenzenesulfonamide;N-{4-(methyloxy)-3-[(3-{[(3-nitrophenyl)sulfonyl]amino}quinoxalin-2-yl)amino]phenyl}acetamide;N-{3-[(4-methylpyridin-3-yl)amino]quinoxalin-2-yl}-3-nitrobenzenesulfonamide;N-(3-{[2,3-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-nitrobenzenesulfonamide;N-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-2-cyanobenzenesulfonamide;3-nitro-N-[3-(1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)quinoxalin-2-yl]benzenesulfonamide;N-[3-(1,3-benzoxazol-4-ylamino)quinoxalin-2-yl]-3-nitrobenzenesulfonamide;N-(3-{[2,6-difluoro-3-(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-nitrobenzenesulfonamide;N-{3-[({3-[(4-fluoro-3-methylphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]phenyl}-N-2-,N-2-dimethylglycinamide;N-{3-[({3-[(3,5-dimethylphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]phenyl}-N-2-,N-2-dimethylglycinamide;N-(3-{[(3-{[2,4-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)-N-2-,N-2-dimethylglycinamide;N-{3-[(3,5-dihydroxyphenyl)amino]quinoxalin-2-yl}-3-nitrobenzenesulfonamide;N-[3-({[3-(2,3-dihydro-1H-inden-5-ylamino)quinoxalin-2-yl]amino}sulfonyl)phenyl]-N-2-,N-2-dimethylglycinamide;N-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-4-[(1-methylethyl)oxy]benzenesulfonamide;N-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)biphenyl-4-sulfonamide;N-[3-({2-chloro-5-[(difluoromethyl)oxy]phenyl}amino)quinoxalin-2-yl]-3-nitrobenzenesulfonamide;and a pharmaceutically acceptable salt or solvate thereof.